Sunday, November 13, 2016

Dr Antonio Bianco 
Rattles Cages in 
Mainstream  Endocrinology

by Jeffrey Dach MD
 
Dr Antonio Bianco asks a very important question, “Does a normal serum TSH indicate adequate treatment in patients given levothyroxine (T4-only) medication?” His answer, published in the Oct 2016 Endocrinology and Metabolism, may rattle a few cages, and is in agreement with what we have been writing for many years now.

Dr Antonio Bianco found levothyroxine (T4) treated patients had difficulty converting T4 into T3, were more likely to be overweight, taking anti-depressants and statins, and had low thyroid symptoms in spite of levothyroxine. Dogmatically clinging to the TSH reference range, and to T4 levothyroxine as the only acceptable thyroid medicine is the error and tragedy of mainstream endocrinology. Dr Bianco’s report has freed endocrinology from the shackles of this false medical dogma. We have written for many years that natural dessicated thyroid (Naturethroid from RLC labs) is a better choice compared to T4 monotherapy with levothyroxine, and that in some cases, suppression of TSH below the reference range is required for relief of symptoms.

Antonio Bianco MD, is an endocrinologist and past president of the American Thyroid Association (ATA) at Rush Medical School in Chicago.  His article is entitled :  Is a Normal TSH Synonymous with “Euthyroidism” in Levothyroxine MonotherapyLeft image Dr Antonio Bianco Courtesy of the NIH.


Dr Antonio Bianco studied 469 patients treated with levothyroxine (T4 only) for hypothyroidism, and compared to normal controls.  He found:

1) Levothyroxine (T4) treated patients ” had higher serum free T4 and lower serum free T3 than healthy or matched controls.”
My comment: T3 (tri-iodothyronine) is the active thyroid hormone, so a lower serum T3 means these patients are having difficulty converting T4 into T3 and may be suffering from low thyroid symptoms in spite of  levothyroxine (T4).

2) Levothyroxine treated patients were more likely to be overweight despite consuming less calories,
My comment: Weight gain is a common symptom of the low thyroid condition caused by slow metabolic rate, and failure to convert calories to energy.  Instead, consumed calories are stored up as weight gain.
3) Levothyroxine patients were more likely to be taking anti-depressants, and anti-cholesterol (statin) drugs compared to matched controls.”  
My comment: Lack of energy, fatigue and depression are common symptoms of the low thyroid condition, all relieved by providing adequate thyroid dosage.  Many publications, including the Hunt Study, showed that elevated serum cholesterol is a symptom of the low thyroid condition.  Providing a higher dosage of thyroid medicine is the correct treatment. This will suppress the TSH,  reduce serum cholesterol and prevent heart attacks.   Instead of giving thyroid medicine, the proper medication, the conventional doctor will commonly prescribe a statin anti-cholestrol drug which will reduce serum cholesterol without treating the low thyroid condition.  This is the terrible tragedy and error of mainstream medicine.

Dr Bianco Speaks Out

Dr Antonio Bianco’s study reports that levothyroxine dosage based on the TSH reference range does NOT necessarily provide symptom relief for many patients.(15-17)  That’s because dosage based on TSH range may be inadequate, and higher dosage with suppression of TSH may be needed for complete relief of low thyroid symptoms.

Suppression of TSH May be Needed For Symptom Relief

We have found that suppression of TSH below the reference range is frequently needed for complete symptom relief in the low thyroid patient.  Although endocrinology dogma  opposes TSH suppression, in actuality, endocrinologists commonly suppress the TSH long term with thyroid medicine in two groups of patients, the post thyroidectomy patients and the thyroid nodule patients.  Numerous published studies show no adverse effects of TSH suppression in both groups.  For more on this see: TSH Suppression Benefits and Adverse Effects

The Low Thyroid Condition – Case Report

Thyroid Gland in NeckMary is a 57 year old female with chronic fatigue, dry, brittle hair, dry skin, muscle aches and pains, and depression, all obvious symptoms of a low thyroid condition. Mary has been to a number of endocrinologists, primary care doctors and even sought advice from her hair stylist. Her latest doctor prescribed a thyroid pill called Levothyroxine (50 mcg) which has done little to relieve her symptoms. In addition, she has depression, and her psychiatrist prescribed an SSRI antidepressant, called Zoloft. She also takes Xanax for bouts of anxiety and insomnia. Mary came into the office frustrated with her conventional medical treatment which was not helping her.

Routine Thyroid Panel

Our routine evaluation includes a full medical history, physical examination and lab panel. Mary’s baseline lab panel showed a TSH of 5.2, a Free T3 of 260 and a Free T4 of 1.4. TPO antibodies were very elevated (1,100) indicating Hashimoto’s Thyroiditis. Her spot urinary Iodine level was 47 mg/dl indicating iodine deficiency (based on World Health Organization Guidelines).

Switching from Levothyroxine to Natural Thyroid

ThyroidRadionuclideScanThyroxineMary was switched from Levothyroxine to Naturethroid from RLC labs and within a week reported improvement in clinical symptoms. Six weeks later Mary’s Naturethroid dosage was gradually increased to Two and a Half Tablets every day (Using one grain tablets of 65 mg each) . Mary reports improvement. She has tapered off her antidepressants, as she no longer needs them.

Going to the OB/Gyne

Ten weeks later, Mary goes to see her OB Gyne doctor for her annual Pap smear and pelvic exam which included a TSH blood test, with a low result (0.1 which is below the reference range RR).

Her OB/Gyne doctor looks at the TSH test result and tells Mary she is taking too much thyroid medicine and needs to cut back. Mary then calls me at my office to relay this information. Two doctors are telling her different things and Mary doesn’t know who to believe. This scenario plays out in my office with a different patient each week.

The reality is that Mary is on the proper dosage of thyroid medication, and we expect to see a low or suppressed TSH result when this occurs.

In Part One of this series, we discussed how treatment of the low thyroid condition with natural thyroid is superior to Levo-thyroxine (also called Synthroid a T4 only medication).

Pig Natural Desiccated Thyroid Naturethroid RLC LabsIn our office we use Nature-throid from RLC labs. (Disclosure: NONE, I have no financial relationship with RLC labs, the manufacturer of Nature-Throid NDT – natural dessicated thyroid pills) .
Natural Thyroid which contains both T3 and T4 is a more robust and safer thyroid medication when compared to T4 only medications such as levothyroxine and Synthroid. This is my assessment, based on 10 years of clinical experience prescribing Naturethroid. In addition, we have found that patients who have converted from Synthroid to Natural Thyroid are much happier with their treatment program. The mainstream medical literature is also in agreement.

In part one of this series, we also discussed how the TSH test is not a reliable indicator of adequacy of treatment.(2) In other words, when the patient is taking the proper dosage of natural thyroid medication with complete relief of symptoms, the TSH will typically fall below the lab reference range, also called a suppressed TSH.

In other words, the TSH will be quite low, and this will disturb the mainstream clinician who mistakenly believes the patient is taking too much thyroid medication. The issue can be settled simply by running a Free T3 test which will show that the Free T3 in the normal range, thus excluding any possibility of a “hyperthyroid state”. Unfortunately, most conventional docs do not have the knowledge to order a free T3 test, and have limited understanding of the thyroid patient.
Suppressive Dose Needed –
The TSH Test is Not a Reliable Monitor

Many patients do quite well on Synthroid. However about 20% (one fifth) of patients on T4 only medications like Synthroid do not do well, and have continued symptoms of a low thyroid condition.(3) Why is that? A miniscule amount of T4 medication such as 50-88 mcg of Levothyroxine may be sufficient to drive down the TSH, and the endocrinologist will then consider treatment dosage adequate. It is not adequate. This is explained by Dr D.S. Oreilly in his articles (4-5), and by Dr. Henry Lindner in his detailed article highlighting why TSH suppression below the lab reference range is needed for adequate treatment for the low thyroid condition. (6)

JapanNuclearAccidentIodineFukushimapowerplant1Japan in Agreement
In agreement is another article, this time from the Center for Excellence in Thyroid Care, Kuma Hospital, Japan in which the authors state that :
“TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy “(9),
Again, knowledgeable physicians are finding that TSH suppression below the lab reference range is required for adequate treatment of the low thyroid condition. In this Kuma Hospital study, doctors found TSH-suppressive doses of Synthroid were needed in post-thyroidectomy patients to achieve the same normal Serum T3 levels which were present on pre-operative labs.

Natural Thyroid
When Natural thyroid medication is used, and the dosage gradually adjusted upwards from 1/2 tab daily to the maintainance dose of two to three of the One Grain (65mg) Tabs daily (usually done over 6 weeks), the lab panel at this time will typically show a TSH which is below the normal reference range, and a free T3 which is in the upper end of the normal range 350-420. The low TSH is to be expected, is not disturbing, and is not indicative of a hyperthyroid state.

Why Has Endocrinology Mismanaged
the Low Thyroid Condition for Fifty Years?

money1The answer is obvious. Follow the money trail. Synthroid is the fourth most prescribed drug in America with 70 million prescriptions. Abbot labs, the makers of Synthroid, uses the massive profits to finance and fund Endocrinology Groups and Societies, their meetings, and clinical research grants. They also fund the key opinion leaders to give lectures at meetings in support of Synthroid and the TSH test. This is all done in spite of the obvious clinical inferiority of T4 only medications such as levothyroxine, and the unreliability of the TSH test to monitor adequacy of treatment. For many decades now, mainstream endocrinology has been completely corrupted by huge cash infusions from Big Pharma. Welcome to America. It’s a great country.

Disclosure: NONE: I have no financial relationship with the makers of natural desiccated thyroid tablets.

Articles With Related Interest

TSH Suppression Benefits and Adverse Effects

New Study Shows Natural Thyroid Better than Synthetic

Ann Nicole Smith and Hypothyroidism
Why Natural Thyroid is Better than Synthetic Part One
Why Natural Thyroid is Better Part Two
The TSH Reference Range Wars – Part One
TSH Wars, Part Two

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
www.drdach.com
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com

Links and References

1) http://www.scielosp.org/scielo.php?pid=S0042-96862002000800007&script=sci_arttext
Bulletin of the World Health Organization
Bull World Health Organ vol.80 no.8 Genebra Aug. 2002
dx.doi.org/10.1590/S0042-96862002000800007
Determining median urinary iodine concentration that indicates adequate iodine intake at population level by François Delange,1 Bruno de Benoist,2 Hans Bürgi,1 & the ICCIDD Working Group3
2) www.ncbi.nlm.nih.gov/pubmed/16416346
TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wien Klin Wochenschr. 2005 Sep;117(18):636-40. Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA. Endocrine Unit, Dept Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece.
The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. 85 – Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. “We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect,“ provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.
2011
3) www.ncbi.nlm.nih.gov/pmc/articles/PMC3148220/ .free full text ….
www.ncbi.nlm.nih.gov/pubmed/21829633
Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients (normal TSH). Dr Damiano Gullo MD – Endocrine Unit, University of Catania Medical School, Catania, Italy PLoS ONE 6(8): Published: August 1, 2011
20% of patient on Synthroid (T4) will have abnormal T3/T4 ratios because they are unable to convert T4 to T3. I say: They need a more physiologic treatment such as natural dessicated thyroid. “More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion.”
Context- Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.
Objective – To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. Setting – Academic hospital.Patients- 1,811 patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.
Measurements – TSH, FT4 and FT3 concentrations by immunoassays.
Results- FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals.
The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.
Conclusions- Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.
2010
4) www.ncbi.nlm.nih.gov/pubmed/20584231
Thyroid hormone replacement: an iatrogenic problem.
Int J Clin Pract. 2010 Jun;64(7):991-4. Dr O’Reilly DS. Department of Clinical Biochemistry, Royal Infirmary, Glasgow, UK.
Abstract Thyroid hormone replacement is one of the very few medical treatments devised in the 19th century that still survive. It is safe, very effective and hailed as a major success by patients and clinicians. Currently, it is arguably the most contentious issue in clinical endocrinology. The current controversy and patient disquiet began in the early 1970s, when on theoretical grounds and without proper assessment, the serum thyrotropin (TSH) concentration was adopted as the means of assessing the adequacy of thyroxine replacement. The published literature shows that the serum TSH concentration is a poor indicator of clinical status in patients on thyroxine. The adequacy of thyroxine replacement should be assessed clinically with the serum T3 being measured, when required, to detect over-replacement.
1986
5) www.ncbi.nlm.nih.gov/pmc/articles/PMC1341585/
Br Med J (Clin Res Ed). 1986 September 27; 293(6550) full text
Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? W D Fraser, E M Biggart, D S O’Reilly, H W Gray, J H McKillop, and J A Thomson
To establish their role in monitoring patients receiving thyroxine replacement biochemical tests of thyroid function were performed in 148 hypothyroid patients studied prospectively. Measurements of serum concentrations of total thyroxine, analogue free thyroxine, total triiodothyronine, analogue free triiodothyronine, and TSH thyroid stimulating hormone, made with a sensitive immunoradiometric assay, did not, except in patients with gross abnormalities, distinguish euthyroid patients from those who were receiving inadequate or excessive replacement. These measurements are therefore of little, if any, value in monitoring patients receiving thyroxine replacement. To stop doing thyroid function tests in these cases would result in considerable savings nationally in the cost of reagents in laboratories using commercial kits.
Article By Henry Lindner MD
6) hormonerestoration.com/files/TSHWrongtree.pdf
Against TSH-T4 Reference Range Thyroidology: The Case for Clinical Thyroidology Henry H. Lindner MD1
The current reliance upon the TSH to both detect hypothyroidism and direct its treatment is illogical and ineffective. Hypothalamic-pituitary function is modified by many known and unknown factors, and is known to deteriorate with age. Even if one could know that a person’s hypothalamic-pituitary response is perfect, one cannot assume that the TSH response to once-daily oral thyroid replacement is identical to the response to continual thyroidal hormone production. The TSH level is only a measure of the hypothalamic-pituitary response to thyroid hormones. It is neither a test of free thyroid hormone levels nor of thyroid hormone effects throughout the body. It is useful for determining the cause of hypothyroidism; not for diagnosing or treating it. The most reliable serum tests of thyroid hormone sufficiency are free T4 and free T3, but their broad laboratory reference ranges are neither optimal nor treatment ranges, and there are marked individual variations. Ultimately, both the diagnosis and treatment of hypothyroidism must be clinical.
7) www.ncbi.nlm.nih.gov/pubmed/11201857
Thyroid. 2000 Dec;10(12):1107-11. Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy?
Tigas S, Idiculla J, Beckett G, Toft A. Source Endocrine Unit, Royal Infirmary, Edinburgh, Scotland.
Abstract There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves’ disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves’ disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves’ disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.
8) www.ncbi.nlm.nih.gov/pmc/articles/PMC143526/
BMJ. 2003 February 8; 326(7384): 311–312. PMCID: PMC143526 full text free
Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey Christian Meier, senior registrar in endocrinology, Peter Trittibach, clinical research fellow, Merih Guglielmetti, statistician, Jean-Jacques Staub, emeritus professor of endocrinology, and Beat Müller, head of division Division of Endocrinology, Department of Medicine, University Hospital, CH-4031 Basle, Switzerland
We found no correlations between the different parameters of target tissues and serum TSH. Our findings are in accordance with a cross sectional study showing only a modest correlation between TSH and the percentage of positive hypothyroid symptoms4 and data showing discordant responses between the pituitary and peripheral target tissues in patients treated with l-triiodothyronine.5 We assume that secretion of TSH is driven by maximal stimulation, with no further increase occurring with greater severity of hypothyroidism. Therefore, the biological effects of thyroid hormones at the peripheral tissues—and not TSH concentrations—reflect the clinical severity of hypothyroidism. A judicious initiation of thyroxine treatment should be guided by clinical and metabolic presentation and thyroid hormone concentrations (free thyroxine) and not by serum TSH concentrations.
TSH suppression required to achieve good result with Synthroid
9) http://www.eje-online.org/content/167/3/373.abstract
TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy by Mitsuru Ito,Akira Miyauchi,Shinji Morita,Takumi Kudo,Eijun Nishihara, Minoru Kihara,Yuuki Takamura,Yasuhiro Ito, Kaoru Kobayashi, Akihiro Miya, Sumihisa Kubota and Nobuyuki Amino from the Center for Excellence in Thyroid Care, Kuma Hospital, 8-2-35, Shimoyamate-Dori, Chuo-Ku, Kobe-City, Hyogo 650-0011, Japan
Objective Thyroidal production of triiodothyronine (T3) is absent in patients who have undergone total thyroidectomy. Therefore, relative T3 deficiency may occur during postoperative levothyroxine (l-T4) therapy. The objective of this study was to evaluate how the individual serum T3 level changes between preoperative native thyroid function and postoperative l-T4 therapy.
Methods We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T4 (FT4), free T3 (FT3), and TSH levels measured preoperatively were compared with those levels measured on postoperative l-T4 therapy.
Results Serum TSH levels during postoperative l-T4 therapy were significantly decreased compared with native TSH levels (P<0.001). Serum FT4 levels were significantly increased (P<0.001). Serum FT3 levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT3 levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT3 levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT3 levels (P<0.001).
Conclusions Serum FT3 levels during postoperative l-T4 therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of l-T4 is required to achieve the preoperative native serum T3 levels in postoperative l-T4 therapy.
10) full text
http://content.karger.com/ProdukteDB/produkte.asp?Doi=339447
Translational Thyroidology / Review
Thyroid Hormone Replacement Therapy: Three ‘Simple’ Questions, Complex Answers
Antonio C. Bianco, Sabina Casula from the Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Fla., USA
Eur Thyroid J 2012;1:88-98
11) http://www.ncbi.nlm.nih.gov/pubmed/22593590
http://jcem.endojournals.org/content/97/7/2256.short
J Clin Endocrinol Metab. 2012 Jul;97(7):2256-71. doi: 10.1210/jc.2011-3399. Epub 2012 May 16.
Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? Biondi B, Wartofsky L. Department of Clinical and Molecular Endocrinology and Oncology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic.
We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action.
The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.
12) http://www.eje-online.org/content/early/2012/11/26/EJE-12-0819.short
Is Pituitary Thyrotropin an Adequate Measure Of Thyroid Hormone-Controlled Homeostasis During Thyroxine Treatment? by Rudolf Hoermann, John E M Midgley, Rolf Larisch and Johannes W Dietrich
Objective. In recognition of its primary role in pituitary-thyroid feedback, thyrotropin (TSH) determination has become a key parameter for clinical decision-making. The present study evaluates the value of TSH as a measure of thyroid hormone homeostasis under T4 therapy.
Design,
Methods. We have examined the interrelationships between free triiodothyronine (FT3), free thyroxine (FT4) and pituitary TSH by means of 1) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of L-T4 and 2) independent mathematical simulation applying a model of thyroid homeostasis, together with a sensitivity analysis.
Results. Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH versus FT3 and FT4 between untreated patients and L-T4 groups. Total deiodinase activity (GD) was positively correlated with TSH in untreated subjects. However, GD was significantly altered and the correlation lost under increasing L-T4 doses. 95% confidence intervals for FT3 and FT4, when assessed in defined TSH concentration bands, differed significantly for L-T4-treated, compared to untreated patients. Higher doses were often needed to restore FT3 levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including a preeminent role of pituitary deiodinase type 2.
Conclusion. The data reveal disjoints between FT4-TSH feedback and T3 production that persist even when sufficient T4 apparently restores euthyroidism. T4 treatment displays a compensatory adaptation, but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.
13) Low Thyroid function associated with heart disease risk
HUNT study
14) http://www.ncbi.nlm.nih.gov/pubmed/18443261
Thyrotropin TSH Levels and Risk of Fatal Coronary Heart Disease- The HUNT Study . Norway Arch Intern Med. 2008;168(8):855-860. Bjørn O. Åsvold, MD; Trine Bjøro, MD, PhD; Tom Ivar L. Nilsen, PhD; David Gunnell, MD, PhD; Lars J. Vatten, MD, PhD (Norway) —
70% increased mortality from Heart Disease in higher TSH range (2.5-3.5) In a Norwegian population TSH Levels measured and pts followed over 8 years for death from heart attack 17, 311 women and 8,002 men (without known thyroid or cardiovascular disease or diabetes mellitus at baseline.) Results: In women the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. Conclusions: (TSH) Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD by 70% .
Antonio C. Bianco M.D.
15) Is a Normal TSH Synonymous with “Euthyroidism” in Levothyroxine Monotherapy? Sarah J. Peterson Ph.D., Elizabeth A. McAninch M.D., and Antonio C. Bianco M.D. Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 W Harrison St; Cohn Building Rm 212; Chicago, IL 60612, USA
Context: Levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism.
Objective: To determine whether LT4 at doses that normalize the serum TSH is associated with normal markers of thyroid status.
Design: Cross-sectional data from the US National Health and Nutrition Examination Survey (2001–2012) was used to evaluate 52 clinical parameters. LT4-users were compared to healthy controls and controls matched for age, sex, race, and serum TSH. Regression was used to evaluate for correlation with serum thyroxine (T4) and triiodothyronine (T3) levels.
Participants: 9,981 participants with normal serum TSH were identified; 469 were LT4-treated.
Results: Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to ∽15–20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants: had higher BMI despite report of consuming less calories/day/kg; were more likely to be taking beta-blockers, statins, and anti-depressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum HDL and lower serum LDL, triglycerides, and CRP. Age was associated with serum free T3:free T4 ratio in all participants; caloric intake was associated in LT4-treated individuals.
Conclusions: In a large population study, participants using LT4 exhibited lower serum T3:T4 ratios and differed in 12/52 objective and subjective measures.
16) Hypothyroidism Symptoms Linger Despite Medication Use, Normal Blood Tests. Study questions value of TSH levels as indicator that disease is under control. Released: 12-Oct-2016 12:05 PM EDT
Source Newsroom: Rush University Medical Center
17) Hypothyroidism symptoms linger despite medication use, normal blood tests October 12, 2016 Rush University Medical Center
New research gives hypothyroidism patients—who often feel dismissed and forgotten—evidence that their persistent symptoms are not just in their heads.
Jeffrey Dach MD
7450 Griffin Road, Suite 190
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Low Thyroid, Hashimotos and Pregnancy

Low Thyroid, Hashimotos and Pregnancy

by Jeffrey Dach MD

Today is a happy day for Susan.  She just delivered a healthy baby girl, and mailed me a cute photo of the baby from her hospital bed,  Six months before, Susan was weeping in my office, recounting her story of repeated miscarriages and fertility problems.  Her lab panel showed a borderline low thyroid status and elevated anti-thyroid antibodies indicating Hashimoto’s Autoimmune Thyroiditis.  Upper Left Image courtesy of wikimedia commons.
After a complete evaluation, we started Susan on our usual program including natural desiccated thyroid One and a Half Grains per day, selenium 400 mcg/day, iodine 450 mcg per day and a good prenatal multivitamin.  That must have done the trick, and Susan’s thank you card has the “pitter patter of little feet” on the cover.

Mother with BabyA Common Scenario

Since ten to twenty per cent of all women of reproductive age have elevated anti thyroid antibodies, we see this scenario quite often.
There are literally thousands of low thyroid Susans ignored by mainstream medicine, left to suffer through repeated miscarriages and other fertility problems, representing yet another tragic error by conventional endocrinology.  Left image mother and baby courtesy of wikimedia commons.

Dr Peter Taylor Makes a Plea

Dr Peter Taylor made exactly this point at a recent Endocrine Society Meeting when he said that more pregnant women would benefit from thyroid hormone treatment to prevent miscarriages and stillborn babies.(8)  His pleas to screen all pregnant women were ignored, as they have been for many years.(9)  Further studies show that many women with thyroid anti-bodies have better pregnancy outcomes when treated with thyroid hormones.(10,11)

mother with baby
The New York Times Gets the Story Right

A few years back in 2009,  Dr Alex Stagnaro-Green gave the New York Times an accurate accounting of the role of thyroid in pregnancy. (1) These are Dr Green’s points:
1)  Pregnancy is like a stress test for the thyroid. increasing thyroid hormone requirement by 50%
2) Hypothyroidism during pregnancy is linked to miscarriage (5), and preterm delivery. (5)  Compared to aged matched controls, children of hypothyroid mothers have lower I.Q.s by seven points on average when tested  seven to nine years later. (3)  Nineteen per cent of these children had IQ’s of 85 or less.(3)
3) Even though thyroid hormone levels may be completely normal, the presence of Hashimoto’s anti-thyroid antibodies is associated with a 200-300% increase of miscarriage.
Dr. Roberto Negro from Italy published a study in 2006 of women who were thyroid antibody-positive.  Treatment of these women with thyroid hormone resulted in a dramatic reduction of stillbirths and preterm deliveries.(4)  Upper left image courtesy of wikimedia commons.

How to Make Smarter Babies

As mentioned above, children born to hypothyroid mothers, have lower IQ when tested 7-9 years later.  Giving thyroid hormones to the mother makes smarter babies.(3)  In addition, maternal iodine deficiency is associated with reduced educational outcomes in the offspring.(14)  This is precisely why we screen women for iodine levels, and make sure they have adequate iodine supplementation. In  Hashimotos patients, we use low-dose iodine supplementation of 225-450 mcg per day which is a safe level.
Dana Trentini Hypothyroid MOMHypothyroid MOM

Perhaps the one person most dedicated to getting this message out is Dana Trentini who runs HypoThyroid Mom.  (left image courtesy of Dana Trentini Hypothyroid MOM.
After suffering through a miscarriage herself, she discovered the importance of thyroid in pregnancy,  and has been a tireless advocate ever since.   Regretting her misplaced trust in doctors who failed to treat her low thyroid condition, HypothyroidMom now encourages all women to take charge of their thyroid health.  The EcoFeminist Blog run by Aimee picks up and amplifies this message in her article,  hypothyroidism and miscarriage.
Conclusion: Another tragedy of modern endocrinology is the manner in which the hypothyroid mom is ignored, leading to unnecessary suffering.  All pregnant women should be screened for thyroid antibodies and more pregnant women should be treated with thyroid hormones which will result in reduction in miscarriages, reduction in preterm infants, and improvement in IQ and educational outcomes in the newborn
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663

Articles with Related Interest
Why Natural Thyroid is Better than Synthetic
TSH SUppression Benefits and Adverse Effects
How to Make Smarter Children with Iodine Supplementation
The Unreliable TSH Part One
The Unreliable TSH Part Two
Hashimotos, Iodine and Selenium

Links and references

1)  http://www.nytimes.com/ref/health/healthguide/esn-hypothyroidism-expert.html?pagewanted=all
Pregnancy and the Thyroid New York Times  3/13/2009
By INGFEI CHEN  Dr. Alex Stagnaro-Green is a professor of medicine and obstetrics and gynecology at Touro University College of Medicine in Hackensack, N. J. He was a member of an international panel of experts convened by the Endocrine Society that issued a clinical practice guideline in 2007 on managing thyroid dysfunction during pregnancy and after childbirth.
It turns out that pregnancy is like a stress test for the thyroid: the amount of thyroid hormone that needs to be released during pregnancy is increased by about 50 percent, and that’s because of some of the hormones related to pregnancy. If there is a dysfunction with the thyroid, it has been linked — especially hypothyroidism — to miscarriage, preterm delivery, and also with decreased I.Q. in the unborn child when tested at 7 to 9 years old. Furthermore, if a woman has Hashimoto’s disease with antibodies, but with the thyroid hormone levels still being normal, that’s also been associated with a two- to threefold increase of miscarriage. So that’s why all this is very important.
But the women who were antibody-positive who didn’t get the thyroid hormone had a miscarriage rate that was four times higher.
First I educate her that about 50 to 60 percent of women who have thyroid disease and are on thyroid hormone replacement therapy will need an increase in the hormone very early in the first trimester. I explain that this is extremely important so as to prevent complications like miscarriage. And therefore we try to adjust the thyroid hormone level before a woman gets pregnant so that she’s clearly in the normal range.
Secondly, as soon as they get pregnant, I have my patients call me immediately to get thyroid function tests so that I can modify their dose as early as possible in the pregnancy. Bottom line is that as soon as a woman knows she is pregnant she should be tested and see her doctor.
2) https://www.ncbi.nlm.nih.gov/pubmed/2118190
JAMA. 1990 Sep 19;264(11):1422-5.
Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies.
Stagnaro-Green A1, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF. Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029.
We screened 552 women who presented to their obstetrician in the first trimester of pregnancy using highly sensitive enzyme-linked immunosorbent assays for the presence of thyroglobulin and thyroid peroxidase autoantibodies and found an incidence of positivity of 19.6%. The tendency to secrete detectable levels of thyroid autoantibodies was significantly correlated with an increased rate of miscarriage. Thyroid autoantibody-positive women miscarried at a rate of 17%, compared with 8.4% for the autoantibody-negative women. Individual levels of thyroglobulin and thyroid peroxidase autoantibodies were similarly related to this increased miscarriage rate, with no evidence of autoantibody specificity in the relationship. Furthermore, the increase in miscarriages could not be explained by differences in thyroid hormone levels, the presence of cardiolipin autoantibodies, maternal age, gestational age at the time of maternal entry into the study, or previous obstetric history. We conclude that thyroid autoantibodies are an independent marker of “at-risk” pregnancy.
3) https://www.ncbi.nlm.nih.gov/pubmed/10451459
N Engl J Med. 1999 Aug 19;341(8):549-55.
Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.
Haddow JE1, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ.
When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child’s neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known.
METHODS:In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance.
RESULTS:The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism.
CONCLUSIONS:Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.
4) https://www.ncbi.nlm.nih.gov/pubmed/16621910
J Clin Endocrinol Metab. 2006 Jul;91(7):2587-91.
Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.
Negro R1, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H.
Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications.
OBJECTIVE:We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects.
DESIGN:This was a prospective study.
SETTING:The study was conducted in the Department of Obstetrics and Gynecology.
PATIENTS:A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)).
INTERVENTION:TPOAb(+) patients were divided into two groups: group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group.
MAIN OUTCOME MEASURES:Rates of obstetrical complications in treated and untreated groups were measured.
RESULTS:At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7).
CONCLUSIONS:Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.
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5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229690/
Maternal Subclinical Hypothyroidism, Thyroid Autoimmunity, and the Risk of Miscarriage: A Prospective Cohort Study
Liu Haixia, Shan Zhongyan, Li Chenyan, Mao Jinyuan, Xie Xiaochen, Wang Weiwei, Fan Chenling, Wang Hong, Zhang Hongmei,
Han Cheng, Wang Xinyi, Liu Xin, Fan Yuxin, Bao Suqing, and Teng Weiping.  Thyroid. November 2014, 24(11): 1642-1649.
ABSTRACT Background: Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage.
Methods: In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks’ gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH+TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5≤TSH<5.22 or 5.22≤TSH<10 respectively). Accordingly, the SCH+TAI group was also stratified into two subgroups (SCH+TAI 1 and SCH+TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks.
Results: Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. 2.2%, aOR 3.40 [CI 1.62–7.15]; p=0.002), isolated TAI (5.7% vs. 2.2%, aOR 2.71 [CI 1.43–5.12]; p=0.003), SCH+TAI 1 (10.0% vs. 2.2%, aOR 4.96 [CI 2.76–8.90]; p=0.000), and SCH+TAI 2 (15.2% vs. 2.2%, aOR 9.56 [CI 3.76–24.28]; p=0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13±3.21 weeks with subclinical thyroid abnormalities vs. 9.33±1.71 weeks with ET; p=0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH+TAI (SCH 1 vs. SCH 2: 10.79±1.77 vs. 9.70±1.47 weeks, p=0.039; SCH+TAI 1 vs. SCH+TAI 2: 9.59±1.97 vs. 8.88±1.24 weeks, p=0.031).
Conclusions: Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage.

6) http://hypothyroidmom.com/what-every-pregnant-woman-needs-to-know-about-hypothyroidism/
What Every Pregnant Woman Needs To Know About Hypothyroidism
October 8, 2012 by Dana Trentini
The launch of my blog Hypothyroid Mom is intentionally timed this October 2012 during Miscarriage Awareness Month in memory of the baby I lost to hypothyroidism and in dedication to my two boys who beat the odds and made it to the world. This is Part 2 of my 5-part series entitled Miscarriage Awareness Month: The Dangers of Hypothyroidism And Pregnancy.
7) https://theecofeminist.com/2016/08/30/hypothyroidism-and-miscarriage/
Hypothyroidism and Miscarriage August 30, 2016     Eco Feminist
Nov 9, 2016  Peter Taylor
8) https://www.sciencedaily.com/releases/2016/11/161109090353.htm
Giving more pregnant women common thyroid medicine may reduce risk of complications.  Date:    November 9, 2016
Source:    Society for Endocrinology
Summary:    Extending the number of pregnant women given the common drug levothyroxine to boost thyroid hormone levels may lead to a reduced number of stillbirths, early caesarean sections and low-weight babies, according to a new study.
In this study, researchers from the University of Cardiff investigated whether pregnant women with mild hypothyroidism and their babies would also benefit from levothyroxine treatment. They combined data from a thyroid screening study and linked it to routinely collected clinical data to study the effect of correcting borderline thyroid function on obstetric outcomes.
The researchers analysed over 13,000 women who were 12-16 weeks pregnant, 518 of whom had mild hypothyroidism. Of these, 263 women received levothyroxine and the rest received no treatment. They assessed the women’s pregnancy outcomes by measuring stillbirth rates, preterm delivery, length of stay at hospital, birth weight and the number of early caesarean sections.
They found that women with mild hypothyroidism treated with levothyroxine had a lower risk of giving birth to low weight babies and were also less likely to undergo an early caesarean. Untreated women with mild hypothyroidism were more likely to have a stillbirth than women with normal thyroid function and no stillbirths occurred in the treated group. However, there was no significant difference between the other obstetric outcomes or when all outcomes were combined.
Our work raises the possibility of providing real benefits from using a safe, cheap and well established treatment by simply extending it to the number of pregnant women we treat,” said Dr Peter Taylor, lead author of the study.
Dr Taylor believes more substantial benefits might be found by treating the pregnant women at an earlier stage than used in this study. “We should consider universal thyroid screening in pregnancy as it compares favourably in terms of cost-effectiveness with other conditions that we currently screen for,” he added.
9) http://www.futuremedicine.com/doi/abs/10.2217/whe.15.7?journalCode=whe
Taylor, Peter N., et al. “Should all women be screened for thyroid dysfunction in pregnancy?.” Women’s Health 11.3 (2015): 295-307.
The subject of universal thyroid screening in pregnancy generates impassioned debate. Thyroid dysfunction is common, has significant adverse implications for fetal and maternal well-being, is readily detectable and can be effectively and inexpensively treated. Furthermore, the currently recommended case-finding strategy does not identify a substantially proportion of women with thyroid dysfunction thus favoring universal screening. On the other hand subclinical thyroid dysfunction forms the bulk of gestational thyroid disorders and the paucity of high-level evidence to support correction of these asymptomatic biochemical abnormalities weighs against universal screening. This review critically appraises the literature, examines the pros and cons of universal thyroid screening in pregnancy, highlighting the now strong case for implementing universal screening and explores strategies for its implementation.
10) http://www.endocrine-abstracts.org/ea/0044/ea0044OC6.3.htm
Endocrine Abstracts (2016) 44 OC6.3
Controlled Antenatal ; Obstetric Outcomes
Peter Taylor1, Arron Lacey2, Daniel Thayer2, Mohd Draman1, Arshiya Tabasum1,3, Ilaria Muller1, Luke Marsh1, Arwel Poacher1, Aled Roberts3, Marian Ludgate1, Alex Rees3, Kristien Boelaert4, Aled Rees1, Shiao Chan4,5, John Lazarus1, Scott Nelson6, Bijay Vaidya7 & Onyebuchi Okosieme1
Context: Suboptimal thyroid function in pregnancy is associated with adverse obstetric outcomes but it is unclear whether levothyroxine treatment, initiated during pregnancy is beneficial.
Design & Participants: Retrospective analysis of the Controlled Antenatal Thyroid Screening (CATS) study with obstetric outcomes obtained through data-linkage in the Secure Anonymised Information Linkage (SAIL) databank. We studied 13,224 pregnant women; 12,608 had normal thyroid function, 340 had subclinical hypothyroidism (SCH), 305 had isolated hypothyroxinemia (IH). 518 women with abnormal thyroid function were randomized to receive levothyroxine (N=263) or no treatment (N=255) at the end of the first trimester.
Main Outcome Measures: Composite measure (primary outcome) of stillbirth, neonatal death, preterm delivery <34 weeks, APGAR score at 5 minutes <7, length of hospital stay >5 days. Secondary analyses included early gestational age (<37 weeks), early caesarean sections (<37 weeks).
Results: In individuals with abnormal thyroid function randomized to treatment or control, treatment had no discernible effect on the composite outcome. 29 events occurred in the untreated group vs 22 in the treated. OR (treated) = 0.75 95%CI (0.40, 1.40). Untreated women with SCH had increased odds of stillbirth compared to women with normal thyroid function OR=4.37 (95%CI 1.04, 18.3). No stillbirths occurred in women on levothyroxine. Untreated women with IH had increased odds of an early gestational age at delivery (<37 weeks) than women with normal thyroid function OR=1.58 (95%CI 1.04, 2.50). Women with IH randomized to receive treatment with levothyroxine had reduced odds of early gestational age at delivery OR=0.37 (95%CI 0.14, 0.99) and early caesarean sections (0% vs 4%) p=0.04 than untreated women.
Conclusion: Both SCH and IH were associated with key adverse obstetric outcomes. Although there was no difference in composite outcome there were some benefits observed with levothyroxine therapy. Larger studies are required to confirm the benefits of screening and treatment in pregnancy.
11) http://www.bmj.com/content/342/bmj.d2616
Thangaratinam, Shakila, et al. “Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence.” Bmj 342 (2011): d2616.
This systematic review was conducted with a prospective protocol with widely recommended methods.15
Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
What is already known on this topic
Thyroid autoantibodies are relatively common in women of reproductive age
Thyroid autoimmunity might be associated with adverse pregnancy outcomes
What this study adds
In women with normal thyroid function and thyroid autoantibodies the risk of miscarriage is more than tripled and the risk of preterm birth is doubled
Treatment with levothyroxine can halve the risk of miscarriage in women with normal thyroid function and thyroid autoantibodies
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12) http://acb.sagepub.com/content/53/4/421.short
Thyroxine replacement: a clinical endocrinologist’s viewpoint
V Eligar1     PN Taylor1     OE Okosieme1,2⇑     GP Leese3     CM Dayan1  1Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK  2Endocrine and Diabetes, Department Prince Charles Hospital, Cwm Taf University Health Board Merthyr Tydfil, UK
3Department of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK
OE Okosieme, University Hospital of Wales Cardiff, UK. Email: OkosiemeOE@Cardiff.ac.uk
Background Hypothyroidism affects 2–5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30–50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval.
Methods This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement.
Results Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited.
Conclusion Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.
13) http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/thyroid_preg.html
Thyroid Hormones: Pregnancy and Fetal Development
Thyroid hormones are critical for development of the fetal and neonatal brain, as well as for many other aspects of pregnancy and fetal growth. Hypothyroidism in either the mother or fetus frequently results in fetal disease; in humans, this includes a high incidence of mental retardation.
Isolated maternal hypothyroidism: Overt maternal hypothyroidism typically is not a significant cause of fetal disease because it usually is associated with infertility. When pregnancy does occur, there is increased risk of intrauterine fetal death and gestational hypertension. Subclincial hypothyroidism is increasingly being recognized as a cause of developmental disease – this is a rather scary situation. Several investigators have found that mild maternal hypothyroidism, diagnosed only retrospectively from banked serum, may adversely affect the fetus, leading in children to such effects as slightly lower performance on IQ tests and difficulties with schoolwork. The most common cause of subclinical hypothyroidism is autoimmune disease, and it is known that anti-thyroid antibodies cross the human placenta. Thus, the cause of this disorder may be a passive immune attack on the fetal thyroid gland.
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14) http://press.endocrine.org/doi/full/10.1210/jc.2012-4249
http://ecite.utas.edu.au/99264
Hynes, Kristen L., et al. “Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort.” The Journal of Clinical Endocrinology & Metabolism 98.5 (2013): 1954-1962.
Iodine is essential for neurodevelopment in utero and in childhood, with deficiency being a major cause of preventable intellectual impairment (1). The serious neurodevelopmental consequences of severe iodine deficiency (ID) on the fetus are well documented and include cretinism, which manifests as motor, cognitive, and auditory defects (2). ID, however, results in a spectrum of disorders with many speculating that even mild maternal ID has subtle impacts on fetal development. Recent reviews are not conclusive as to whether low maternal dietary iodine intake in areas of mild deficiency leads to measurable effects on cognition and neurodevelopment of the offspring (3, 4).
Clinical trials of iodine supplementation in pregnancy in regions of mild ID have typically focused on positive changes in maternal and fetal thyroid function and volumes but have not examined long-term developmental consequences in the offspring. To our knowledge, there are only three studies reporting neurodevelopmental outcomes in offspring after supplementation of mothers with mild ID. Berbel et al (5) reported significantly delayed neurobehavioral performance in children (aged 18 months) if their mothers did not receive iodine supplementation by 4 to 6 weeks of gestation. Similarly, Velasco et al (6) found that children (aged 3–18 months) had higher psychomotor development scores if their mothers were given supplements from the first trimester. Both interventions provide preliminary evidence that even mild gestational ID may have an adverse impact on fetal neurodevelopment and subsequent infant functioning. In contrast, Murcia et al (7) reported that higher maternal intake of iodine-containing supplements was associated with lower scores on the Psychomotor Development Index of the Bayley Scales of Infant Development in their children (aged 1 year).
In addition to gestational studies, there is increasing evidence from observational population studies that less severe cognitive and motor impairment occurs in apparently normal individuals from areas of ID (8). Children without cretinism from iodine-deficient regions of Iran were found to have growth retardation and neurological, auditory, and psychomotor impairments (9). Boyages et al (10) reported impaired intellectual and neuromotor development in apparently normal Chinese children, with a shift in the distribution of cognitive skills to a lower level. Furthermore, randomized controlled trial data show that postgestational supplementation can lead to significantly improved mental performance of children from areas of mild (11), moderate (12), and severe ID (13).
We compared educational outcomes of children (aged 9 years) born to women assessed as being iodine deficient (urinary iodine concentration [UIC] <150 μg/L) or sufficient (UIC ≥150 μg/L) during pregnancy. Gestation occurred during 1999–2001, a documented period of mild ID (median UIC, 77.5 μg/L) in the Tasmanian population (14), with the children subsequently growing up in an environment considered to be replete (14, 15) (median UIC, 108.0 μg/L) after introduction of voluntary iodine fortification (16). We investigate whether mild gestational ID has long-term effects on educational outcomes.
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15) http://www.thyroidmanager.org/question/repeated-miscarriages-in-a-young-woman-with-hashimoto%E2%80%99s-thyroiditis-and-antibodies/
Repeated Miscarriages in a Young Woman with Hashimoto’s Thyroiditis and Antibodies  Last Updated: March 5, 2008 ·   Leslie J. DeGroot, M.D.
Question
This is a 32 yr old female who first saw me 3/7/7 when she was 8 weeks IUP, G4M3. First pregnacy was 5yrs ago FTND. Subsequent 3 miscarriages at 6-8wks IUP. Hypothyroidism diagnosed 3yrs ago, not treated for reasons unclear. 6/06 she was started on LT4 50 mcg, gradually increased to 100mcg by 2/07. When I saw her 3/7/7 – TSH was 6.9 (1st trim N- 0.3-4.5), FT4-1.3, TPO> 1000, TGAb>3000, TSI – 132 (N<125), TBII -30%(n<16%). I increased her LT4 to 112mcg, but she went on to have a miscarriage 5/07 at 12 weeks IUP. Her TSH on f/u post miscarriage was – 0.03, FT41.8, T3 185, TPO> 1000, TGAb1050. I reduced her LT4 back to 100mcg/day.
She also had a tennis ball sized fibroid which was subsequently removed. She has also had extensive testing by her reproductive endo, for etiology for her miscarriages, all which seem negative.
She wants to conceive again.
Since 11/07 her TFT have been normal on LT4 88mcg/day. 2/07 – TSH- 2.87, FT4 1.4, T3-122, TPO>1000, TGAb> 3000.
She weighs 123lbs, and was hyperthyroid on 100mcg LT4.So, I have not changed her current dose.
Is she a candidate for IVIG? Is there anything else I can do from endo standpoint to reduce her risk for miscarriage? What would you advice her?
Radha Reddy, MD
Rancho Cucamonga CA
Response
I am not too familiar with the medical phraseology used in the U.S. when presenting case histories, but I think I understood correctly that this patient has been pregnant 4 times, with three previous miscarriages, and a fourth – and last miscarriage – during her most recent pregnancy in 2007. Obviously, she also has chronic autoimmune thyroiditis, with hypothyroidism diagnosed a couple of years ago. It is not clear to me whether the 3 previous miscarriages took place while she was an untreated hypothyroid patient or whether the obstetrical history occurred before that period (where, by the way, she may also have already been hypothyroid, without a diagnosis). In her most recent pregnancy, the patient received L-thyroxine ‘almost’ from the onset of gestation. However, and despite increasing her l-T4 dosage, the “best” TSH obtained was still clearly suboptimal in the first trimester (6.9 mU/L). After that, she miscarried once again. Finally, the antibody data indicate high titers of anti-Tg (>1000-3000) and anti-TPO (>1000) Abs and a positive TBII value (30% TSH binding inhibition).
Comments:
1) This is the sad – but not unusual – story of those patients who miscarry early (in the first trimester) and repeatedly, who have autoimmune thyroiditis and a not well-controlled thyroid function. Most studies on recurrent abortion in such ‘thyroid’ cases indicate that the best that can be done to help them is to make sure that their thyroid function is perfectly equilibrated before they become pregnant (serum TSH below 2.5 mU/L is probably the best target). In my own practice, I tend to titrate them even ‘higher’, to obtain a serum TSH around 1 mU/L. As soon as they become pregnant (spontaneously or medically-assisted), their thyroid function tests need to be monitored extremely closely to make sure that thyroid function remains entirely normal. This can only be achieved by sequential monitoring (every three-four weeks) of serum free T4 and TSH, with rapid (or even anticipated, as I like to do) increments in L-T4 dosage, and a close follow up until 24 weeks gestation, at least.
2) If this Hashimoto patient also has TSH-receptor antibodies (again from my understanding of the data presented), she may well be one of those rare cases with blocking-type TSHR-Abs. In principle, this should not affect the mother other than enhancing the risk of hypothyroidism, but could constitute a risk for fetal thyroid function during the second half of pregnancy (if she ever gets to that point !).
3) She may well be a candidate for IVIG (in addition to L-T4?). This decision is usually taken by our Ob-Gyn colleagues. The rate of pregnancy success with IVIG in the study by E. Vaquero (Amer J Reproductive Immunology in 2000) was improved (54.5%) but less than with l-T4 administration (81.2%). However, that study was not randomized nor controlled and the number of cases in each branch was small (see my Editorial with this article on pages 202-203).
4) I have followed personally a small number of women with the similar difficult medical conditions. Some have undergone medically-assisted procreation, some have even eventually adopted children, and despite these heavy antecedents, we have witnessed a few (but remarkable) successes since some women finally achieved natural conception and successful outcome of pregnancy (after many failed attempts) by treating adequately their Hashimoto’s disease. Thus, there is still hope since the patient is only 32 years of age, but this of course is not to say that success is obtained in all those cases !!
I hope my comments will be helpful to you.
Prof Daniel Glinoer
University of Brussels

16) https://www.holtorfmed.com/thyroid-miscarriage/
Subclinical Hypothyroidism and Thyroid Antibodies Increase Risk of Early Miscarriage  .  by Holtorf Medical Group

17) http://www.stopthethyroidmadness.com/2012/11/28/hypothyroidism-pregnancy-dangerous/
Ladies: Hypothyroidism in pregnancy can be dangerous, says this woman who suffered a miscarriage
November 28, 2012  By Janie Bowthorpe
18) Endocrine Society (2012, June 23). Mild thyroid dysfunction in early pregnancy linked to serious complication. Newswise. Retrieved July 3, 2012 from http://www.newswise.com/articles/mild-thyroid-dysfunction-in-early-pregnancy-linked-to-serious-complications
19) Allan, W.C., J.E. Haddow, G.E. Palomaki, J.R. Williams, M.L. Mitchell, R.J. Hermos, J.D. Faix, R.Z. Klein. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7:127-130. Retrieved from http://171.66.127.126/content/7/3/127.full.pdf
20) Rao VR, Lakshmi A, Sadhnani MD. Prevalence of hypothyroidism in recurrent pregnancy loss in first trimester. Indian J Med Sci 2008;62:357-61. Retrieved from http://www.indianjmedsci.org/text.asp?2008/62/9/357/43122

21) http://drclark.typepad.com/dr_david_clark/2011/11/thyroid-antibodies-and-risk-of-miscarriage-premature-birth.html
Thyroid Antibodies and Risk of Miscarriage, Premature Birth
TriangleThyroidDoctor.com
Dr. David Clark, DC -Center for Low Thyroid Solutions Durham, NC- explains a hidden cause of why many women suffer miscarriages and premature births.

Link to this article: http://wp.me/p3gFbV-3UK

Jeffrey Dach MD
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Sunday, April 10, 2016

Artemisinin our Ultimate Cancer Weapon a Gift from China

Artemisinin our Ultimate Cancer Weapon a Gift from China

Tu You You Artemesinin_China_Daily2Artemisinin our Ultimate Cancer Weapon a Gift from China
by Jeffrey Dach MD
Beating Colon Cancer with Artemisinin
Susan, a 56 year old house wife, noticed abdominal pain and change in bowel habits.  An X- Ray test revealed Susan has colon cancer (lower left image), with a typical apple core  appearance on barium enema.  Susan was sent to a colon cancer surgeon who told her she needed an operation to remove the cancer from her colon. Left image: Tu You You winner of 2015 Nobel Prize in Medicine Courtesy of China Daily News. This article is part one, for part two click here.

Artemisinin Prospective Randomized Trial in Colon Cancer
Apple_Core_Colon_Cancer_Barium_Enema_artemesininSusan read in the newspaper about Dorothy Bradshaw, a colon cancer patient who participated in a clinical study with Dr. Sanjeev Krishna at St George University London in 2010.(71)
Dorothy took a new anti-cancer drug called Artesunate (an artemisinin derivative) for two weeks before her colon resection to remove the tumor.  Five years later, she is alive and well.  This randomized study was done with 20 colon cancer patients awaiting surgery.  Half received the Artesunate pill for two weeks prior to surgery, and the other half a placebo.  Five years later, there were 6 cancer recurrences in the placebo group, but only one in the Artesunate (Artemisinin) group. There were no deaths in the Artesenate group, compared to three deaths in the placebo group.(70-71)  I was very impressed by this.
Susan called me to ask if Artemisinin could improve her chances of beating cancer recurrence after surgery.   I said to Susan,Artemisinin is our ultimate weapon against cancer, a gift from China”
Left Image Artemisinartemesinin chemical structure_2in chemical structure. Active portion of molecule is the endo-peroxide bridge (red arrows) highly reactive oxygen bridge which reacts with the iron in malaria organisms, and the iron in cancer cells.
Ridiculing Chinese Herbs
Back in the old days when I was hospital based physician, we took lunch in the doctor’s dining room where conversation included amazement and ridicule at the stories of patients who took Chinese herbs for their medical condition.  The surgeons had a good laugh, expressing amazement that any intelligent American would choose to take a Chinese herb for a medical condition.  Below image: Dr. Tu YouYou wins Nobel prize in Medicine 2015 for discovery of Artemisinin. Image Courtesy of IFLScience and China’s Daily .
Artemisinin – A Gift From The Chinese GovernmentTu You You Artemesinin_China_Daily_2015_Nobel _PrizeBack in the 1960’s during the Vietnam War, the North Vietnamese soldiers succumbed to malaria in great numbers.  This military issue prompted the Chinese government  to develop better and more effective anti-malarial drugs.  China enlisted the help of a young medical student named, Dr Tu YouYou  who began working.   She uncovered an ancient Chinese medical text in an archaeological excavation written by  Ge Hong (281–340 AC), which describes an herbal tea, sweet wormwood, to treat fevers and chills.  This sweet wormwood tea was later mentioned in the 1596 Chinese Compendium by Li Shizen.   Dr Tu Youyou ultimately isolated the active molecule in the tea, called artemisinin (figure 1 above), an effective anti-malaria drug, for which she received the 2015  Nobel prize in Medicine.  Artemisinin and derivatives like artesunate are now life saving malaria drugs used by millions. Who’s laughing at Chinese Herbs Now?
Antimalarial Drugs are Also Anti-Cancer Drugs 
artemesinin_reacting_with_HemeLeft Upper Image: Artemisinin reacting with Heme courtesy of O’neill, et al  Molecular Mechanism of Action of Artemisinine Debate ONeill 2010. (131)

Dr. Das reports in a 2015 article that Artemisinin (or derivatives) are effective against 55 cancer cell lines with inhibitory effects against pancreatic cancer, osteosarcoma, lung cancer, colon, melanoma, breast, ovarian, prostate, central nervous system, lymphoma, leukemia and renal cancer cells. (1)
The molecular mechanism by which artemisinin compounds serve as effective anti-cancer agents can be found in its molecular structure, the endo-peroxide bridge which reacts with the iron molecule. (see figure 1 above)
Cancer Cells Contain Massive Amounts of Iron (Fe)
We can exploit key metabolic differences between cancer cells and normal cells, to come up with ways to kill cancer cells, while leaving normal cells unharmed as discussed in a previous article, cancer as a metabolic disease.  This is the targeted non-toxic approach to cancer treatment.  One such key metabolic difference is the higher Iron (Fe) content of cancer cells.
Heme_Artemesinin_alkylation_fenton_ironLeft Image shows endo-peroxide bridge (oxygen) in Artemisinin (1) attaching to Heme iron (Fe) (2) courtesy of  Robert et al,  “Characterization of the alkylation product of heme by the antimalarial drug artemisinin.” (132)
Cancer Cells Contain Massive Amounts of Iron in Lysosomes
Cancer cells express high levels of the transferrin receptors for internalizing iron (Fe) at a tremendous rate.(21)  This is a useful difference from normal cells.  The cancer cells have a voracious appetite for Iron, and contain massive quantities of iron compared to normal cells.  In addition, the transport mechanism for iron in cancer cells, called transferrin receptors are massively up-regulated.(18)   In fact, a correlation between expression of transferrin membrane receptor and Ki-67 (a marker of tumor proliferation) has also been reported,(19)  The more aggressive the tumor, the greater number of transferring receptors.  This difference in iron content and iron transport is why artemisinin compounds kill cancer cells selectively while sparing normal cells.
Heme_Porphyrin_RingAddition of Iron Enhances Killing Effect of Artemisinin
Left image: Schematic of Hemoglobin Molecule with Central Fe (Red).  This Fe is Iron in the center of Heme Molecule .Courtesy of wikimedia.
Since the anti-cancer effect of artemisinin relies on presence of Iron in the cancer cell, its effects are up-regulated 1.5-10 fold by the addition of iron, as you might expect.(20)
Fenton Reaction in Lysosomes – Ferroptosis
What are lysosomes? Lysosomes are the cell organelles which contain acid used for digestion and degradation of unwanted intracellular debris and endocytosed bacteria and proteins.    For example, our white cells,  called neutrophils, kill bacteria in our blood stream by eating them.  Once eaten,  these unwanted proteins are digested in lysosomes,  The acid in the lysosome is produced by a molecular machine called the “V-ATPase”, a molecular pump for acid production.  Lysosomes often accumulate large amounts of iron, especially in cancer cells, which may then react with oxygen, called Fenton reaction, causing release of hydroxyl radicals.  This compromises the lysosomal membrane with release of acid contents freely into the cell cytosol initiating a form of cell death is called “ferroptosis” (53)  (as opposed to apoptosis), as we will detail below. (5)  In this scenario,  Artemisinin enters the cancer cell lysosomes, which already contain iron as a degradation product from ferritin.  The endoperoxide oxygen bridge in artemisinin reacts with iron , the Fenton Reaction, and hydroxyl radicals are produced.  The diagram below illustrates the mode of action of Artemisinin in the cancer cell.
Mode of Action of Artemisinin Cancer Cell Death from Yang et al.(6)
Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin YANG 2014 Fig F9BFigure 9E from Yang et al. Artemisinin enters cancer cell along with iron loaded ferritin. Both enter the lysosome which then triggers mitochondria reactive oxygen species (ROS) and caspase 3 programmed cell death.(6)
Cancer Cell Killing Mechanism according to Yang et al:
Firstly Artemisinin (ART) accumulates in the lysosomes. Second, ART increases lysosomal acidification, cathepsin enzyme activity, and protein degradation via promoting lysosomal V-ATPase assembly.   ART induces autophagy, based on the observations that ART increased autophagosomes formation and enhanced autophagic flux.
“We believe that this perinuclear clustering of lysosomes is, in fact, an indication of autophagy induction.  We observed increase of mitochondrial ROS implicating lysosomal  iron as a critical mediator in ART-induced mitochondrial ROS production and cell death. It is possible that enhanced lysosomal degradation of ferritin induced by ART leads to the transient increase of cytosolic ferrous iron, which then affects the mitochondria, leading to enhanced mitochondrial ROS production.”(6)
BAF (bafilomycin A1), a lysosomal (V)-ATPase inhibitor, was able to effectively inhibit the cell death induced by ART .  “Ferritin delivery and degradation in lysosomes is required for the toxicity of ART. Therefore, lysosomal inhibitors significantly protect the cells from ART-induced cell death via blockage of ferritin degradation.”(6)
Chloroquin inhibits Ferritin Degradation and Cell Death induced by ART
“In fact, we also found that chloroquine inhibited the ferritin degradation and cell death induced by ART as efficiently as BAF (data not shown).”
BAF is a lysosomal inhibitor which prevents artemisinin cell death.  DFO is iron chelator which inhibits cell death. NAC (N acetyl cysteine inhibits ROS )inhibits cell death. Images courtesy of Yang, Nai-Di, et al. (6)  “Artesunate induces cell death in human cancer cells “
Lysosomal Clustering and Accumulation At Nucleus
When Artemisinin enters the cancer cell, it causes a peculiar re-arrangement of the lysosomes and mitochondria in a pattern typical for autophagy (the cell eats itself and dies) as reported by Dr Brady (see below).  This peri-nuclear clumping has also been observed in experiments which knock out KIF5B, the only microtubule motor protein associated with the lysosomes.  Therefore it has been speculated that the effect of Artemisinin in the lysosome is to impair the microtube motor proteins.  This perinuclear clustering of organelles is a prelude to programmed cell death.
Left image: Top Row are Artemesinin_perinuclear clusterine_auto_phago_lysosomes_2Untreated Breast Cancer Cells showing lysosomes (dark stained particles) dispersed throughout cells.
Bottom Row,  Breast cancer cells treated with Artemisinin. Yellow arrows point to peri-nucelar clustering of autophagosomes (lysosomes).
Images from Figure 3 courtesy of Hamacher-Brady, Anne, et al.(80) “Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production.” J. Biol. Chem 2011.286 (2010): 6587-6601.
Artemesinin_Breast_Cancer_Study_24Left Image shows  Breast Cancer Cells (Top row, yellow arrow) treated with artemisinin and holotransferrin demonstrating clustering of mitochondria (green) and lysosomes(red).  Normal breast cells (lower row) show no clustering effects.  Images from Figure 9 courtesy of Hamacher-Brady, Anne, et al.(80)
Dr Kundu reports in a 2015 article in Acta tropica that many anti-malarial drugs serve as anti-cancer drugs and vice versa (22).      Curcumin, resveratrol, pterostilbene, allicin (from garlic) are among the many natural substances that work together in synergy with Artemisinin.  In addition, Artimisisin, and derivatives, enhance the anti-cancer activity of most conventional chemotherapy agents.(22)
Artemisinin Derivatives and Ferritin Tagging
Efficacy of Artimisinin may be impaired by poor absorption and relatively low blood level.  How can the potency and efficacy of Artemisinin be increased ?  Make a derivative such a artemether, artesenuate.  Derivatives are modified artemisinin compounds possessing greater bio-availability and potency.   Be careful here because greater bio-availablity and potency may be associated with increased toxicity which we will discuss below.
Transferrin Tagged Artemisinin
Another technique is to tag the Artemisin molecule with transferrin, the Iron carrier protein.  This combination had greater anti-cancer potency  see Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation.  Nakase. (83)
Other Anti-Cancer Treatments Work in Synergy
Firstly,  intra-cellular iron is required for Artemisinin to kill the cancer cell. Having the patient take an Iron supplement (such as Iron bis-glycinate, Optferrin Pure Encapsulations) increases the effect of the Artemisinin.  However on should be careful to take the iron supplement at a different time from the Artemisinin to avoid reacting directly with the iron in  the GI tract.   Most Artemisinin practitioners will use a schedule to allow “rest days”.  The Artemisinin is taken 14 days,   and then take 4 days off.  This is thought to improve GI absorption.
Additional anti-cancer supplements work synergistally with artemisinin. These include Vitamin D, Iodine (iodoral)  Berberine, Curcumin (lipospheric) (24-29), Resveratrol, Pterostilbene, Allicin, Melatonin, Sulphoraphane, Butyrate and high dose vitamin C, fresh juicing with organic carrots and organic beets,  Lipo-Colostrum (Soveriegn Labs), a good multivitamin (One Multi Pure Encapsulation) . (79)
Artemisinin-Curcumin Synergy
In a 2006 study using malaria infected cultured RBC;s, the combination of artemisinin with curcumin was found to synergize.(56)  This combination showed greater malaria killing activity than the individual compounds.  The molecular pathways were not elucidated.  One might anticipate a synergistic effect for this combination in killing cancer cells.  However, to my knowledge this has not yet been studied, and would be a good topic for NIH funding for future research.(56)
Artemisinin – Allicin (Garlic) Synergy
Synergistic Anticancer Effect Artesunate with Allicin OsteosarcomaAllicin,(diallyl thiosulfinate) the active ingredient in garlic, has known anti-cancer effects.  Allicin induces caspase mediated apoptosis in lymphoma and other cancers.  Dr Jiang (see Left Image) reported in 2013 the synergistic combination of Artesunate (artemisinin derivative) with allicin had a heightened anti-cancer effect on osteosarcoma cell lines in vitro and in vivo.(57) Left Image Fig 3B from Jiang showing synergistic effect of combining Artesunate (an Artemisin derivative) with Allicin.   Bar Chart shows apoptosis levels after treating Osteosarcoma cells (in culture) with Artesunate (green arrow), Allicin (blue arrow) or combination of Artesunate and Allicin (Red Arrow). (57)  Dr Jiang also reported additional mouse tumor xenograft studies were done, and these in-vivo studies also showed enhanced synergy for the combination of Allicin and Artesunate. (57)
Platelet Inhibition
Allicin,and thiosulfinates, are potent platelet-aggregation inhibitors which can aggravate bleeding, so caution is advised when used with other platelet inhibitors such as Feverfew, Aspirin, Vitamin E, Fish Oil   or  ibrutinib (Imbruvica – Bruton’s-Kinase Inhibitor).
Synergy Artemisinin with Resveratrol
Synergic effects of artemisinin and resveratrol in cancer cellsIn 2014, Drs Li and Yang reported a synergistic effect of the combination of Resveratrol with Artemisinin in Hepatoma (HepG2) and Cervical Cancer (HeLa) cell lines. The combination significantly increased apoptosis and necrosis of the two cancer cell lines. (58) Left Image Bar Chart from Li and Yang showing cancer cell death (apoptosis) after treatment with Artemisinin (green arrow), Resveratrol (blue arrow) and the Combination (red arrow) for two cancer cell lines (black and grey bars).(58)
Although Pterostilbene was not used in this study, the Pterostilbene is a derivative of Resveratrol, chemically similar with better bioavailability, and I would therefore expect Pterostilebene to demonstrate an even greater synergy with Artemisinin compared to Resveratrol.  A 2005 study by Dr Tolomeo showed the 3-Hydroxy Pterostilbene to be 50-100 times stronger than Resveratrol in killing multi-drug resistance leukemia cells. However, the plain pterostilbene was the least toxic to normal hematopoetic cells. (59)
Synergy of Artemisinin with Butyrate (76, 122-128)

Synergistic Cytotoxicity Artemisinin Sodium Butyrate Human Cancer CellsDr Lai reports in 2005 that the cancer cell killing effect of Artemisinin is enhanced with the addition of butyrate, a short chain fatty acid.(76)  Their study used a lymphoblastic leukemia cell line, treated with a combination of dihydroartimisin and butyrate.
Left Image Bar Chart courtesy of Dr Lai 2005,   Cell Count after treatment with Dihydroartemisinin(Green Arrow), after Butyrate (blue Arrow), After Combination (Red Arrow) 
In a 2007 report, Dr Pajak  outlined the molecular basis of anti-cancer effects of butyrate. (123)  Butyrate, a small four-carbon chain fatty acid, is a normal product of large bowel microbial fermentation of dietary fiber.  Butyrate inhibits (HDAC) histone deacetylase activity, allowing DNA binding of several transcription factors which increases expression of proapoptotic genes, and results in amplification of apoptotic pathways (programmed cell suicide) in the cancer cell, while sparing normal cells.
In a 2013 report, Dr JK  Fauser studied the anticancer effects of butyrate and coconut oil (lauric acid) on a colon cancer cell line. Dr Fauser reported butyrate induces apoptosis by:” inhibiting histone deacetylase activity, inducing cell cycle arrest, promoting differentiation, activating NF-κB, downregulating α 2 β 1 , modifying glucose availability, and inducing caspase activation in colon cancer cell.” (125)
Dr Choi reported in a 2006 study on the anti-cancer effects of butyrate on a leukemia cell line.(124)  Dr Choi found that butyrate induced apoptosis of human leukemic cells by inhibition of telomerase activity.  In addition, butyrate served as a (HDAC) histone deacetylase inhibitor, resulting in dose-dependent apoptosis associated with up-regulation in pro-apoptotic Bax expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL.(124)
In a 2006 report Dr Heider studied the effect of the HDAC, sodium butyrate, on three Mantle Cell Lymphoma types.  Dr Heider reported butyrate induced potent programmed cell death (apoptosis) of all three Mantle Cell Lymphoma types in a dose-dependent manner. (136)
Buy Sodium Butyrate on Amazon. Link to a review. A probiotic named Clostridium butyricum is known to produce butyrate  This is available from Japan in a product called “Miyarisan” available on Amazon.  It is also contained in  Advanced Orthomolecular Research AOR Probiotic 3.
Targeting (Progenitor) Cancer Stem Cells
Cytotoxic chemotherapy may be quite useful for controlling hematologic cancers such as lymphoma and leukemia.   Although highly toxic, and frequently associated with adverse effects, these drugs may induce complete remission (CR), with disappearance of tumor masses and clearing of radionuclide activity on a follow up PET scans.  In the more aggressive cell types, relapse with metastatic disease is inevitable.  Relapse is thought caused by cancer stem cells (progenitor cells) which are dormant and not actively replicating.  These cancer stem cells are insensitive (resistant) to cytotoxic chemotherapy which is not effective for non-replicating cells. (86-88) Are there natural non-toxic targeted therapies which target cancer stem cells?
Yes, and here they are a few of the many:  Berberine, Resveratrol, Vitamin D3, Curcumin, Feverfew, and Sulforaphane.  (89-90) These are natural substances that target cancer stem cells as discussed by Dr Yanyan Li in his 2011 article :  which also includes soy isoflavone, epigallocatechin-3-gallate, lycopene, piperine, and vitamin D3. (134)
FeverFew – Targeting Cancer Stem Cells – Depleting Glutathione

The well known anti-migraine botanical , Feverfew (parthenolide) has been found to target the cancer stem cells.(74)  The authors state:
Parthenolide preferentially targets AML progenitor and stem cell populations….The molecular mechanism of Parthenolide- with inhibition of nuclear factor κ B (NF-κB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of Parthenolide triggers Cancer Stem Cell-specific apoptosis and as such represents a potentially important new class of drugs for Cancer Stem Cell-targeted therapy.”(74)
Feverfew (Parthenolide) is a widely used botanical which exerts potent anti-cancer effects by blocking nuclear activation of Nuclear Factor Kappa Beta (NFKB), and depleting the cancer cell of glutathione, rendering it sensitive to ROS (reactive oxygen species) which triggers apoptotic pathways. (92-108)   Parthenolide shares some similarities in chemical structure with Artemisinin. One might speculate that the two agents might work synergistically together with enhanced cancer cell killing effects, and this would be a good topic for NIH funding and future study. (92-108)
Sulforaphane – Targeting Cancer Stem Cells and Depleting Glutathione
The active ingredient in broccoli is sulforaphane, a widely used nutritional supplement with no adverse effects.  Sulforaphane has been widely studied as an effective anti-cancer agent which targets cancer stem cells and depletes glutathione in the cancer cell, thus rending it more sensitive to oxidative damage.(109-115)
Dr Yanyan Li, et al reported in 2010 that sulforaphane eliminated breast cancer stem cells in vivo in a mouse xenograft model.  Tumor bearing primary mice were treated with sulforaphane.  The tumor cells from the primary mice were then re-implanted into secondary mice, showing no growth of tumor cells, indicating the cancer stem cells has been eradicated. (112)  I was impressed by this.  A 2012 study by Dr Rodova showed Sulforaphane is effective anti cancer treatment for pancreatic cancer stem cells via blockade of hedgehog signalling.(135)
Other Re-Purposed Drugs that may Work with Artemisisin:
Sulfasalazine_Ferroptosis_Cancer_Cell_Cystine Sulfasalazine (Asulfadine)- an old anti-inflammatory drug widely used in rheumatology,  inhibits the active transport of cystine into the cancer cell. (39-46) (116-121)
When the cancer cell is deficient in cystine, it cannot make glutathione, the intra-cellular anti-oxidant.  Lack of anti-oxidant protection leads directly to “ferroptosis” in cancer cell studies.(see image at left).(39-46)
Left above image: schematic of sulfasalazine blocking cystine uptake by cancer cell, thereby inducing Ferroptosis. Courtesy of Dixon et al., “Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death ”. Cell, vol 149, pp. 1060‒1072 (2012).
Sulfasalazine has a long history of use for inflammatory bowel disease and rheumatoid arthritis.  Benefits are thought to arise from its ability to suppress nuclear factor Kappa Beta.
Sulfasalazine is also a potent suppressor of lymphoma cells on the basis of  suppression of cystine uptake which impairs antioxidant defense. Dr Gout found that sulfasalazine suppressed 90% of lymphoma xenografts in mice, a remarkable finding.  (41)  In addition, sulfasalazine inhibits growth of mantle cell lymphoma in a murine MCL model as reported by Dr Bebb in 2003 Blood.
Since “Ferroptosis” is also seen when cancer cells are treated with Artemisinin, one might logically assume the two drugs Artemisinin and Sulfasalazine would be synergistic, augmenting cancer cell death.  Unfortunately, the appropriate cell culture studies (in-vitro or in-vivo) have not yet been done.  This would be a good study for NIH funding of further research.(39-46)
Chloroquin
Hydroxychloroquine (Plaquenil) and Chloroquine (Avelan), are old anti-malarial drugs.  They serve as lysosomal inhibitors. (47-52)  Pretreatment with chloroquin augmented the cancer killing effect of artemisinin in a 2014  cancer cell study by Dr Ganguli et al.

However, a prior cell study by Dr Hamacher-Brady, found that  concurrent chloroquin  treatment (at the same time) as artemisinin impaired cancer cell killing activity.(80)  Dr Nai-Di Yang also found that Chloroquin inhibited the effect of artemisinin in his study, similar to the activity of the lysosomal V-ATP-ase inhibitor, Baflinomycin. See: Yang, Nai-Di, et al. (6)  “Artesunate induces cell death in human cancer cells “
So, it is clear that simultaneous or concurrent use of chloroquin together with Artemisinin should be avoided, as this inhibits the cell killing effects.  Rather, as suggested by Dr Ganguli et al., it might be appropriate to use the chloroquin drug as a pre-treatment.  In other words, take the chloroquin during one of the OFF-DAYS when the patient is not taking the artemisinin.  A typical artemisinin schedule is 14 days on and 4 days off, (although this may vary).  So, taking the chloroquin during the days off would serve as a pre-treatment for the next Artemisinin cycle as suggested by Dr Ganguli et al.
Chloroquin and has a long track record of safety in treatment of rheumatoid arthritis at a dosage of 250 mg daily for years.  The most worrisome toxicity relates to ocular and macular toxicity at high doses over long periods of time.  The use of a small dose of 250 mg of chloroquin once a week prior to the start of a 5 day course of artemisinin is considerably less than usual chloroquin dosage for rheumatologic disease, and therefore considered safe. Usual chloroquin dosage for travelers prevention of malaria is one 500 mg tablet once a week starting one week before departure, and continuing for 4 weeks after returning. Although higher doses may have retinal toxicity, typical prophylactic doses are considered not harmful to the retina.
Sequential, and not concurrent, use of Chloroquin might ultimately prove to be effective for augmenting the anti-cancer effect of Artemisinin.  I would like to see mouse xeno-graft tumor validation studies of this combination.  However, as far as I know, these types of in-vivo studies have not been done.  This would be a good subject for NIH funding of future research.(47-52)
Mefloquin (Lariam)
Mefloquin was found to be superior to Chloroquin in a 2012 report by Dr Sharma who found Mefloquin caused cell death in breast cancer cell cultures.  In a 1992 report by Dr Glaumann, Mefloquin caused expansion of lysosomes in rat livers starting at 24 hours after administration and lasting for 7 days.  The lysosomes later harbored multi-lamellar bodies which disappeared after 7-10 days.
Mefloquin – Acute Myelogenous Leukemia (17)
Dr M Sukhai et al. reported in their 2013 article  “Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.  Dr Sukhai screened a library of 100 on and off patent drugs for activity against AML (acute luekemia).  At the top of the list was Ivermectin (see below), and the second most acive was the anti-malarial drug mefloquin which selectively killed a panel of leukemia cells and leukemia stem cells in mice.(17)
Mefloquin – Malaria Prophylaxis for Travelers
Mefloquin is currently recommended for malaria prophylaxis in travelers. Dosage is usually on 250 mg tablet per week for a few weeks prior to the trip.  Toxicity: There may be neuro-psychiatric symptoms of toxicity reported by some.  Artemisinin has been used in combination with Chloroquin or Mefloquin for decades, however long term use can result in neurotoxicity,  so caution is advised.
Artemisinin Synergy with Other Chemotherapies – Rituximab
The anti-CD-20 monoclonal antibody, rituximab, has revolutionized the treatment of lymphoma, by targeting the CD20 protein on B cell membranes, and increasing response and survival rates.  Artemisinin has been given with rituximab with good synergism and increased anticancer activity.
See: Sieber, Sebastian, et al. “Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate.” International journal of oncology 35.1 (2009): 149-158.  Combination treatment of malignant B cells Rituximab and Artesunate Sieber Sebastian Int j oncology 2009
Artemisinin Safety and Toxicity

A case report of elevated liver enzymes in an Artemisinin user was reported in 1999.  Therefore, it is prudent to monitor liver enzymes in patients on long treatment.   Neurotoxicity of the more potent artemisinin derivatives has been reported in studies using animals (dogs and mice.).  Anecdotal reports of cerebellar toxicity have been reported in humans.  In spite of this,  Artemisinin is remarkably safe as demonstrated in this study of 242 Vietnamese human subjects who showed no brain stem adverse effects after multiple courses of artemisinin (or its derivatives) for malaria treatment.  Another study, looking at post mortem neuropathology also found no evidence of neurotoxic effects.
Reproductive Toxicity of Artesunate:   In a 2011 study by Dr Olumide and in a later 2014 study, long term administration to mice of the more potent artemisinin derivative, artesunate, induced reversible infertility, with reduced sperm counts.
Cannabinoid Extracts Have Anti Cancer Activity – See my previous article on the use of cannabis extracts in treatment of cancer.   Cannabis extracts have a long history of beneficial use in chemotherapy patients for relief of nausea, and increase appetite effects.  There is also a pain relief effect from cannabis extracts.  Another unexpected benefit is the anti-cancer effects of cannabis are substantial, especially in Leukemia and Lymphoma cells which are specifically sensitive to cannabis extracts as they express increased CB1 and CB2 cannabinoid receptors.  Numerous research studies show that Cannabinoid extracts and ligands induce apoptosis (programmed cell death)  in cancer cells via ceramide accumulation. (30-38)
Is there synergism and augmentation of anti-cancer effects with cannabis extracts and artemisinin compounds ?  Taken in together combination, would cannabis extracts increase the anti-cancer effect of artemisinin ?   This would be a good topic for NIH funding of future research.  My best guess is that future research studies will demonstrate this is indeed the case.
Medicinal Use of Cannabis Extracts have been approved in 23 states so far. If you reside in one of these states, then you may qualify as a medicinal cannabis patient and may legally obtain medicinal cannabis according to your specific state law.  A reputable source for high quality medical grade cannabis oil is Mara Gordon of Aunt Zelda’s Dispensary in San Fransisco, California.  (note: I have no financial relationship with Aunt Zeldas)  .  For more on information, see my book on Amazon: Cannabis Extracts in Medicine
Gleditsia sinensis – Korean thorn
This natural plant botanical has shown anticancer activity.  Possible synergy with artemisinin might be explored. (60-61)
Ivermectin (62-68)  (Stromectol for humans and Ivomec for Dogs)

heartgard_Dog_canine_ivermectinThe 2015 Nobel Prize in Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovery of Ivermectin, the Wonder Drug From Japan,   a well known anti-parasitic agent used to treat “billons” of pets and livestock around the world. (62-68)
Left image : Ivermectin (HeartGuard)   for dogs. Image Courtesy of  All Four Paws .
In humans, Ivermectin is well known as treatment for Lice (Pediculosis) and Scabies (Mites).   Ivermectin also treats parasites such as Nematodes, Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis.
In  2010, Dr Sharmeen published his study. (62)  He screened a long list of drugs looking for cytotoxicity to leukemia cells, and discovered  ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines, while sparing normal cells.  He then studied three mouse models of leukemia showing that tumor growth was delayed “at drug concentrations that appear pharmacologically achievable“(62)
Dr Sharmeen reported ivermectin blocks the glutamate-gated chloride channels, increases intracellular chloride ion concentrations and cell size of leukemia cells.  This causes plasma membrane hyperpolarization.  Ivermectin also increased (ROS) reactive oxygen species in cancer cells functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with conventional chemotherapy agents, ARA-C (cytarabine) and Adriamycin (anthracycline drug also known as Daunorubicin) to increase ROS, reactive oxygen species production. (62)
Ivermectin Cancer Cell Death MechanismAbove image: mechanism of Ivermectin induced caner cell death from Fig 7 Model of P2X4/P2X7/Pannexin-1-induced cancer cell death. Draganov 2015
Dr Dobrin Draganov reported in 2015 that Ivermectin “kills mouse and human triple-negative breast cancer (TNBC) cells through augmented  P2X7-dependent purinergic signaling associated with caspase-1 and caspase-3 activation.”   …”also involved is the recruitment and activation of T cells, macrophages and dendritic cells, a form of immunomodulation and cancer immunotherapy.”
In 2014, Dr Alice Melotti  reported that Ivermectin inhibits the WNT‐TCF pathway in cancer cells. further elucidating the molecular mechanism of cancer cell death.(130)  In a colon cancer cell model, Dr Melotti found Ivermectin effective at micromolar concentrations against both tumor bulk as well as cancer stem cells.  The authors suggested ivermectin,” might be useful as a routine prophylactic agent, for instance, against colon cancer  in familial polyposis, or to prevent nascent cancer in the general aging population.” (130)  I was astonished by this statement.
Some aggressive cancers have a high relapse rate due to cancer stem cells which are resistant to conventional chemotherapy.  Targeting the WNT pathway successfully eliminated cancer stem cells in a Mantle Cell Lymphoma cell line.(133)
Cannabinoids also inhibit cancer cells via the WNT-TCF signalling, so there may be some overlap in similar mechanisms.  Interestingly, Lithium stimulates hippocampal neurogeneisis through the WNT pathway.
Safety and Dosage of Ivermectin
About 200 million are currently taking Ivermectin as treatment/prevention of river blindness.  According to Dr. Crump, Ivermectin is “astonishingly safe for human use.” He says “Indeed, it is such a safe drug, with minimal side effects, that it can be administered by non-medical staff and even illiterate individuals in remote rural communities,”   
Dr Guzzo reports in 2002, no indication of associated CNS toxicity for Ivermectin doses up to 10 times the highest FDA-approved dose of 200 microg/kg.(120 mg single dose is 10 times the 12 mg recommended dose). There was better absorption with higher plasma levels when the drug is taken with food.
Ivermectin dosage for treatment of head lice (pediculosis) is Two Tablets, each one given a week apart,  tablet size is 200 mcg/kg (12 mg tablet for a 60kg male).(137)  As much as 11 single dosages of 150 mcg/kg may be safely repeated every three months, however higher dosing (800 mcg/kg) every three months was associated with opthalmological complaints. (138)

Ivermectin Synergy with Artemisinin ?
Ivermectin and Artemesin have been safely used in combination (ACT) for treatment of malaria.  Would Ivermectin combined with Artemisinin serve as anti-cancer treatment ?  The two agents use differing mechanisms to accomplish the same thing, selectively increasing (ROS), reactive oxygen species, inside the cancer cell. The Artemsinin works via Fenton reaction, the oxidation reaction with iron, while the Ivermectin acts on Chloride Ion channels. Would the two agents enhance each others cell killing effects, working in synergy ?  This would be an excellent topic for future study with NIH funding.

Conclusion:

In my opinion, with the state of our knowledge of  non-toxic targeted agents, malignant cancer is now a curable disease, and suffering or death from cancer should become a thing of the past.  We have discussed Artemisinin, the Chinese anti-malaria drug, which is also a targeted non-toxic anti-cancer agent.  The Artemisinin endoperoxide bridge reacts with iron in the cancer cell to produce oxidative free radicals, which induce apoptotic pathways.  Down regulating the glutathione system with sulfasalazine, allicin (from garlic), Feverfew (parthenolide) or sulforaphane (from Brocolli) renders the cancer cell more susceptible to oxidative damage from Artemisinin and augments the cancer cell killing effects.   Combinations of these agents may prove useful, and should be funded for future NIH research. We have discussed Ivermectin, an astonishingly safe drug taken by 200 million people, with potent anti-cancer effects, at micromolar concentrations, for both tumor bulk as well as cancer stem cells.
The cancer patient of today may not have the luxury of time, and may be inclined to proceed before prospective randomized studies are completed.  Indeed, prospective randomized trials may never be forthcoming due to the nature of the drug discovery and approval system in the US.
Even though Artemisinin and co-agents are considered relatively safe, there may be toxicity at higher dosage, and the user must remain vigilant, and reduce dosage should toxicity occur.  It is recommended that you work closely with a knowledgeable clinician.
Credit and Thanks goes to Robert Jay Rowen, MD  who brought Artemisin to my attention in a 2002 article in Townsend letter: Artemisinin: From Malaria to Cancer Treatment .
Thanks to Stephen Levine, PhD, founder of Allergy Research Group for introducing high quality Artemisinin products for the general public.
This article is part one, for part two click here.

Financial Disclosure:  I have none.  I receive no monetary inducements from, nor have any financial interests in any manufacturer of artemisinin products.
Buy Allergy Research ARTEMISININ on Amazon
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Sources for Artemisinin and Derivatives

Artemisinin Products:  Hepalin.com
Artemix (Artesunate 50mg, Artemisinin 50mg, Artemether 40mg combo) contains 30 capsules in a bottle:$60
Link to :Useful Artemisinin information page
Articles with related interest
Cancer as a Metabolic Disease
How do Cannabinoids Kill Cancer Cells
Artemisinin Support Group on Facebook
Jeffrey Dach MD
Links and References
video by Dr Henry Lai – May 2014
artemisinin- discovered by chinese in 1970’s used as anti-malaria compound.  Used for 30 years with safe profile.  Leukemia cell will pick up 1000 times more iron than a normal cell.  Artemisinin is approximately 100 times more potent in killing leukemia cells than normal lymphocytes.  Similar results for breast cancer cells.
Artemesisnin is very selective against cancer cells, Effective at low dose.  Few side effects.  Oral capsule. Inexpensive. 1-2  mg/kg per day effective in treating cancer, (in animals)

Discovery of Artemisinin video
The 2011 Lasker~DeBakey Clinical Medical Research Award honors a scientist who discovered artemisinin and its utility for treating malaria. Tu Youyou (China Academy of Chinese Medical Sciences, Beijing) developed a therapy that has saved millions of lives across the globe, especially in the developing world. An artemisinin-based drug combination is now the standard regimen for malaria, and the World Health Organization (WHO) lists artemisinin and related agents in its catalog of “Essential Medicines.” Each year, several hundred million people contract malaria. Without treatment, many more of them would die than do now. Tu led a team that transformed an ancient Chinese healing method into the most powerful antimalarial medicine currently available.

Nobel Prize in Medicine for Discovery of Artemisinin Video  Published on Dec 8, 2015
Youyou Tu delivered her Nobel Lecture on 7 December 2015 at Aula Medica, Karolinska Institutet in Stockholm. The lecture was presented in Mandarin.
Youyou Tu: Discovery of Artemisinin – A gift from Traditional Chinese Medicine to the World
Artemisinin 2015 free
1) Das A K. Anticancer effect of antimalarial artemisinin compounds. Ann Med Health Sci Res [serial online] 2015 [cited 2016 Feb 13];5:93-102.
Anticancer activity of artemisinin has been demonstrated primarily in vitro and in animal models. In a study, testing 55 cell lines showed that artesunate showed inhibitory effects against leukemia, colon, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cells. [39] The semisynthetic derivative DHA showed remarkable antineoplastic activity against pancreatic, leukemic, osteosarcoma, and lung cancer cells. [40] Moreover, artemisone was superior to artemisinin and showed better synergism with other anti-cancer agents. [41]
Furthermore, artesunate proapoptotic effect is not affected in a doxorubicin-resistant leukemia cell line; rather it potentiates doxorubicin’s apoptotic effects. [8]
how the antitumor activity is exerted following artemisinin activation is still not well-understood but is associated with multiple mechanisms, including reactive oxygen species (ROS), oxidative DNA damage, sustained DNA double-strand breaks, and apoptosis. A better understanding of common mechanisms under similar conditions in different cell systems will greatly help developing targeted artemisinin derivatives.
Experimental evidences, mostly animal studies indicate that artemisinins and its derivatives may be a therapeutic alternative in the future, particularly in highly metastatic and aggressive cancers without developing drug resistance.
2011
2)  Mercer, Amy E., et al. “The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials.” Journal of Biological Chemistry 286.2 (2011): 987-996.
2012
3)  J Biomed Biotechnol. 2012; 2012: 247597. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug.   Maria P. Crespo-Ortiz 1 ,* and Ming Q. Wei 2
Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells. Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity. In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis. In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression. However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects. The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated. The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.
2015
4) Hongbao, Ma, Margaret Ma, and Yang Yan. “Cancer and Artemisinin Research Literatures.”  Cancer Biology, 2015;5(3),   Brookdale Hospital, Brooklyn, New York 11212, USA; 2 Cambridge, MA 02138, USA  Hongbao Cancer Artemisinin Research Cancer Biology 2015 .  Nice listing of research articles
2015  Iron-dependent cell death – Ferroptosis(53)
5)  Ooko, E., et al. “Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells.” Phytomedicine: international journal of phytotherapy and phytopharmacology 22.11 (2015): 1045.
The ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine led to a significantly reduced cytotoxicity of artenimol, indicating ferroptosis as cell death mode. Treatment with ferroptosis-inducing agents such as artemisinin derivatives represents an attractive strategy for cancer therapy.
2014 Lysosomal Degradation of Ferritin
Cell mechanisms of artemisinin
6) Yang, Nai-Di, et al. “Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin.” Journal of Biological Chemistry 289.48 (2014): 33425-33441.  (full free)
Artesunate (ART) is an anti-malaria drug that has been shown to exhibit anti-tumor activity, and functional lysosomes are reported to be required for ART-induced cancer cell death, whereas the underlying molecular mechanisms remain largely elusive. In this study, we aimed to elucidate the molecular mechanisms underlying ART-induced cell death. We first confirmed that ART induces apoptotic cell death in cancer cells.
Interestingly, we found that ART preferably accumulates in the lysosomes and is able to activate lysosomal function via promotion of lysosomal V-ATPase assembly. Furthermore, we found that lysosomes function upstream of mitochondria in reactive oxygen species production. Importantly, we provided evidence showing that lysosomal iron is required for the lysosomal activation and mitochondrial reactive oxygen species production induced by ART. Finally, we showed that ART-induced cell death is mediated by the release of iron in the lysosomes, which results from the lysosomal degradation of ferritin, an iron storage protein. Meanwhile, overexpression of ferritin heavy chain significantly protected cells from ART-induced cell death. In addition, knockdown of nuclear receptor coactivator 4, the adaptor protein for ferritin degradation, was able to block ART-mediated ferritin degradation and rescue the ART-induced cell death. In summary, our study demonstrates that ART treatment activates lysosomal function and then promotes ferritin degradation, subsequently leading to the increase of lysosomal iron that is utilized by ART for its cytotoxic effect on cancer cells. Thus, our data reveal a new mechanistic action underlying ART-induced cell death in cancer cells.
Repression of NFkB – stimulates autophagy
7) Hu, Wei, et al. “Dihydroartemisinin induces autophagy by suppressing NF-κB activation.” Cancer letters 343.2 (2014): 239-248.
Nuclear factor-kappa B (NF-κB) and autophagy are two major regulators involved in both tumor initiation and progression. However, the association between these two signaling pathways still remains obscure. In this work, we demonstrate that dihydroartemisinin (DHA) stimulates the induction of autophagy in several cancer cell lines through repression of NF-κB activity. We also show that inhibiting NF-κB results in an accumulation of reactive oxygen species (ROS), which participate in the stimulation of autophagy. These findings present a pathway by which DHA promotes autophagy in cancer cells and provide evidence for the DHA-induced sensitization effect of some chemotherapeutics.
8) Toyokuni, Shinya. “Iron and thiols as two major players in carcinogenesis: friends or foes?.” The Changing Faces of Glutathione, a Cellular Protagonist (2015): 114.  Toyokuni Shinya Iron thiols carcinogenesis Cellular Protagonist 2015
Leukemia 2012
9) Wang, Zeng, et al. “Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity.” FEBS open bio 2 (2012): 103-112.
In summary, DHA induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity,
which includes the down-regulation of TfR expression and induction of apoptosis through the mitochondrial pathway.
Artemisinin synergistic with Resveratrol
10) Li, Peichun, et al. “Synergic effects of artemisinin and resveratrol in cancer cells.” Journal of cancer research and clinical oncology 140.12 (2014): 2065-2075.
The aim of this study was to investigate whether resveratrol (Res) combined with artemisinin (ART) possess synergistic effect on different cancer cells.
MATERIALS AND METHODS:The viability of HepG2 and HeLa cells treated with ART and Res was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Combination index (CI) analysis and isobologram were used to assess the synergistic effect of ART and Res in different ratios. Wound-healing assay was used to investigate the migration rate. AO staining and fluorescent microscopy measurements were performed to detect the cell apoptosis. Reactive oxygen species (ROS) was measured with 2’7′-dichlorofluorescein diacetate (DCFH-DA).
RESULTS:MTT assay indicated that ART and Res inhibited the growth of HeLa and HepG2 cells in a dose-dependent manner. The combination of ART and Res exhibited the strongest anticancer effect at the ratio of 1:2 (ART to Res). The combination of the two drugs also markedly reduced the ability of cell migration. Apoptosis analysis showed that combination of ART and Res significantly increased the apoptosis and necrosis rather than use singly. Additionally, ROS levels were elevated by combining ART with Res.
CONCLUSIONS:Taken together, the present study suggested that ART and Res possessed the synergistic anti-tumor effect. ART in combination with Res could be an effective therapeutic strategy for cancer.
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11) Berdelle, Nicole, et al. “Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells.” Molecular cancer therapeutics 10.12 (2011): 2224-2233.
12) Chen, Kai, et al. “Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells.” Anti-cancer drugs 25.6 (2014): 652-662.
We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells. ART arrested the cell cycle in the G2/M phase, which was accompanied by an upregulation of p21. ART upregulated the expression of Beclin1, an initiator of autophagy (type II programmed cell death). In addition, ART stimulated the aggregation of LC3, which is considered to be a marker of autophagosome formation. We further verified the transformation of LC3 from type I into type II. 3-MA, a classical autophagy inhibitor, attenuated ART-induced autophagosome formation, cell growth repression, G2/M arrest, and p21 upregulation. Autophagy induction and p21 upregulation were also repressed by knockdown of Beclin1. Furthermore, ART sensitized breast cancer cells to the chemotherapeutic agent epirubicin through an autophagy-dependent cascade. Our study showed that ART induced autophagy in breast cancer cells and indicated that the anticancer effects of ART were exerted through an autophagy pathway. Moreover, ART sensitized breast cancer cells to epirubicin chemotherapy. Our results provide a basis for further development of ART as a novel therapeutic agent for the treatment of breast cancer.
Patents  Dr Henry Lai
13) Use of artemisinin and its derivatives in cancer therapy US 20100279976 A1
Abstract  A method for treating cancer in a mammal includes administering to the mammal in need thereof a therapeutically effective amount of artemisinin (ART) or its derivative, such as dihydroartemisinin (DHA), artemether (ARM), or artesunate (ARS) alone or in combination with a chemotherapeutic agent, such as gemcitabine and carboplatin. A method for inhibiting tumor cell proliferation includes contacting a tumor cell with ART or its derivative, such as DHA, ARM, and ARS, in an amount effective to inhibit tumor cell proliferation or in combination with a chemotherapeutic agent, such as gemcitabine and carboplatin.
Dr Henry Lai
full pdf free
14) http://www.ncbi.nlm.nih.gov/pubmed/22935909
Lai, Henry C., Narendra P. Singh, and Tomikazu Sasaki. “Development of artemisinin compounds for cancer treatment.” Investigational new drugs 31.1 (2013): 230-246.
Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents.
artemisone  2011
15) Cancer Chemother Pharmacol. 2011 Mar;67(3):569-77.
In vitro study of the anti-cancer effects of artemisone alone or in combination with other chemotherapeutic agents.  Gravett AM1, Liu WM, Krishna S, Chan WC, Haynes RK, Wilson NL, Dalgleish AG. anticancer effects of artemisone 2011 Gravett
Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting both alone and in combination with established chemotherapeutic agents.
METHODS:The anti-proliferative effects of ART and ATM were tested on a panel of human cancer cells in vitro using the methylthiazoletetrazolium assay, and the effect on cell cycling established by flow cytometry. Immunoblot analyses were performed to determine effects at the molecular level. Finally, ART and ATM were combined with the common anti-cancer agents oxaliplatin, gemcitabine and thalidomide.
RESULTS:ART and ATM caused dose dependent decreases in cell number. ATM was consistently superior to ART, with IC50 s significantly lower in the former. Neither drug caused significant changes to the cell viability (%viable cells >95%), but arrested cell cycling. Blockade was either exclusively at the level of G1, or at all phases of the cell cycle, and associated with reductions in cyclin D1, CDK4 and pRb. Combination studies showed the anti-proliferative effect of ATM was often enhanced by addition of the other drugs, whilst ART exhibited antagonistic properties.
CONCLUSIONS:ART and ATM are active in cancer cell lines, with ATM displaying the greater anti-proliferative effect when used alone. ATM also enhances the effects of the above drugs, with ART being less likely to improve activities. Taken together, ATM should be thought of as the ART-derived compound next in line for further study.
16) Lai, Henry, et al. “Artemisinin-transferrin conjugate retards growth of breast tumors in the rat.” Anticancer research 29.10 (2009): 3807-3810. Lai Henry Artemisinin transferrin conjugate retards breast tumors 2009
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AML – antimalarial agent mefloquine – Kills stem cells
17)  Sukhai, Mahadeo A., et al. “Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” The Journal of clinical investigation 123.1 (2013): 315-328.
To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice.
Would mefloquin act synergisticaly with artemisinin ?
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transferrin receptors over-expressed in mantle cell lymphoma
18) Cancer Res. 2007 Feb 1;67(3):1145-54.
Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments.  Lepelletier Y1, Camara-Clayette V, Jin H, Hermant A, Coulon S, Dussiot M, Arcos-Fajardo M, Baude C, Canionni D, Delarue R, Brousse N, Benaroch P, Benhamou M, Ribrag V, Monteiro RC, Moura IC, Hermine O.
Herein, we show that TfR is highly expressed on MCL cells,
The emergence of tumour-specific, molecularly targeted agents signifies a paradigm shift in cancer therapy.    Taken together with immunohistochemistry data from MCL patients, these results reveal the high level of TfR expression in MCL cells in vivo and in vitro.
Interestingly, the combined effect of A24 with VP-16 or with ara-C was significantly more pronounced than that of any of these agents alone. This difference was more markedly observed in EBV− cells ( Fig. 3B and C). Thus, A24 showed an inhibiting effect on MCL cell proliferation that was both comparable with and synergistic with conventional chemotherapeutic agents.
In spite of recent progress in MCL treatment, the disease prognosis remains poor mainly due to the intrinsic resistance of malignant cells to conventional chemotherapy ( 37– 39), and virtually, all patients, even those who exhibit complete response, will relapse.
19) http://leukemiaandlymphoma.eu/molecular-biology-mantle-cell-lymphoma-profiling-studies-new-therapeutic-strategies/fulltext
Obrador-Hevia, Antònia, et al. “Molecular biology of mantle cell lymphoma: from profiling studies to new therapeutic strategies.” Blood reviews 23.5 (2009): 205-216.
Transferrin receptor
Prevention of MCL establishment by routing the transferrin receptor toward intracellular lysosomal compartments has been shown in an in vitro model. 137 In fact this is an interesting approach that merits further clinical studies for rapidly growing tumour cells such as some MCL forms. Transferrin receptors are highly expressed in rapidly growing tumours including MCL but not in their normal counterparts. These tumours require transferrin for growth and survival. Therefore, impairing the function of these iron uptake receptors promotes apoptosis, and the activation of caspase 3 and 9 has been reported to account for this effect. 137 A correlation between expression of transferrin membrane receptor and Ki-67 has also been reported, 137 suggesting that this protein could represent an interesting target. The implementation of this new therapeutic modality is favoured even further by the fact that synergism with active cytotoxic drugs in MCL has been found, such as ara-C (Aracytine) or VP-16 (Etoposide). 137 It has also been reported that the transferrin receptor gene is up-regulated in MCL relapses. 138 Accordingly, multiple therapeutic avenues can be envisioned including the design of radioimmunoisotypes, or coupling of monoclonal antibodies targeting this receptor with cytotoxic agents.
addition of iron renders artemsisin more cytotoxic
20) Free Radic Biol Med. 2004 Oct 1;37(7):998-1009.ENHANCEMENT OF CYTOTOXICITY OF ARTEMISININS BY FERROUS IRON KAINA 2004
Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron.
Efferth T1, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Häfer R, Stamminger T, Oesch F, Kaina B, Marschall M.
Iron(II) heme-mediated activation of the peroxide bond of artemisinins is thought to generate the radical oxygen species responsible for their antimalarial activity. We analyzed the role of ferrous iron in the cytotoxicity of artemisinins toward tumor cells. Iron(II)-glycine sulfate (Ferrosanol) and transferrin increased the cytotoxicity of free artesunate, artesunate microencapsulated in maltosyl-beta-cyclodextrin, and artemisinin toward CCRF-CEM leukemia and U373 astrocytoma cells 1.5- to 10.3-fold compared with that of artemisinins applied without iron. Growth inhibition by artesunate and ferrous iron correlated with induction of apoptosis. Cell cycle perturbations by artesunate and ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53 mutated WTK1 lymphoblastic cells showed that mutational status of the tumor suppressor p53 did not influence sensitivity to artesunate. The effect of ferrous iron and transferrin was reversed by monoclonal antibody RVS10 against the transferrin receptor (TfR), which competes with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed TfR in 95 and 48% of the cell population, respectively, whereas TfR expression in peripheral mononuclear blood cells of four healthy donors was confined to 0.4-1.3%. This indicates that artemisinins plus ferrous iron may affect tumor cells more than normal cells.
iron in cancer cells
21) Kwok, Juliana C., and Des R. Richardson. “The iron metabolism of neoplastic cells: alterations that facilitate proliferation?.” Critical Reviews in Oncology/Hematology 42.1 (2002): 65-78.
For many years it has been known that neoplastic cells express high levels of the transferrin receptor 1 (TfR1) and internalize iron (Fe) from transferrin (Tf) at a tremendous rate. Considering the high requirement of neoplastic cells for Fe, understanding its metabolism is vital in terms of devising potential new therapies. Apart from TfR1, a number of molecules have been identified that may have roles in Fe metabolism and cellular proliferation. These molecules include transferrin (Tf), the oestrogen-inducible transferrin receptor-like protein, transferrin receptor 2 (TfR2), melanotransferrin (MTf), ceruloplasmin, and ferritin. In the present review these latter molecules are discussed in terms of their potential functions in tumour cell Fe metabolism and proliferation. Further studies are essential to determine the specific roles of these proteins in the pathogenesis of cancer.
Cancer cells generally have higher numbers of the TfR1 than their normal counterparts [[3], [4], [5]] and take up Fe at a higher rate [[6], [7], [8]]. This is reflected by the ability of tumours to be radiolocalized using 67Ga [9], that binds to the Tf Fe-binding site and is delivered via its binding to the TfR1 [[4], [10]].
22)  Kundu, Chanakya Nath, et al. “Anti-malarials are anti-cancers and vice versa–One arrow two sparrows.” Acta tropica 149 (2015): 113-127.Antimalarials are anticancers Kundu Acta tropica 2015
Transferrin Factor Synthesized in Testicles, kidney, spleen
23) J Biol Chem. 1980 Oct 25;255(20):9523-5. Sertoli cells synthesize and secrete transferrin-like protein.Skinner MK, Griswold MD. Sertoli cells of the testes synthesize Tf to provide proliferating spermatocytes with Fe [71].    kidney, spleen also.
Curcumin anti-cancer Effects
24)  Hasanali, Zainul, Kamal Sharma, and Elliot Epner. “Flipping the cyclin D1 switch in mantle cell lymphoma.” Best Practice & Research Clinical Haematology 25.2 (2012): 143-152.
Curcumin, a plant flavonoid that is available naturally in turmeric and as an herbal supplement, has been shown in vitro to downregulate cyclins D1 and D3 at both the transcriptional and post-transcriptional levels in MCL and MM cell lines [50] . Curcumin is known to inhibit the COP9 signalosome, a multiprotein complex similar to the proteasome [51], [52], and [53]. Our laboratory has demonstrated that curcumin and bortezomib synergize in downregulating protein levels of cyclins D1 and D3 in MM and MCL cells [35] . Clinical trials of this agent in combination in lymphoid malignancies alone or in combination with bortezomib are ongoing.
Curcumin against Four MCL cell lines
25) Shishodia, Shishir, et al. “Curcumin (diferuloylmethane) inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.” Biochemical pharmacology 70.5 (2005): 700-713. Biochem Pharmacol. 2005 Sep 1;70(5):700-13.
Shishodia S1, Amin HM, Lai R, Aggarwal BB.
Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin’s lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL’s resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL.
26) Choudhuri, Tathagata, et al. “Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner.” Journal of Biological Chemistry 280.20 (2005): 20059-20068.   All of these data suggest that curcumin can exert its apoptogenic effect in those cells whose cyclin D1 expression is deregulated due to genetic manipulations.
27) Singh, Amareshwar TK, et al. “Curcumin nanodisk-induced apoptosis in mantle cell lymphoma.” Leukemia & lymphoma 52.8 (2011): 1537-1543.
28) Tadmor, Tamar, and Aaron Polliack. “Mantle cell lymphoma: curcumin nanodisks and possible new concepts on drug delivery for an incurable lymphoma.” Leukemia & lymphoma 52.8 (2011): 1418.
29) Yallapu, Murali M., Meena Jaggi, and Subhash C. Chauhan. “Curcumin nanomedicine: a road to cancer therapeutics.” Current pharmaceutical design 19.11 (2013): 1994.
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Cannabinoid Extracts Anti-Cancer Effects
30) Semin Cancer Biol. 2011 Nov;21(5):313-21. The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas. Wasik AM1, Christensson B, Sander B.
The initiating oncogenic event in mantle cell lymphoma (MCL) is the translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic aberrations are necessary for an overt lymphoma to arise. Like other B cell lymphomas, MCL at some points during the oncogenesis is dependent on interactions with other cells and factors in the microenvironment. The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed at low levels on non-malignant lymphocytes and at higher levels in MCL and other lymphoma subtypes. In this review we give an overview of what is known on the role of the cannabinoid receptors and their ligands in lymphoma as compared to non-malignant T and B lymphocytes. In MCL cannabinoids mainly reduce cell proliferation and induce cell death. Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL. The signalling to death has been partly characterized. Even though cannabinoid receptors seem to be expressed in many other types of B cell lymphoma, the functional role of cannabinoid receptor targeting is yet largely unknown. In non-malignant B and T lymphocytes, cannabinoid receptors are up-regulated in response to antigen receptor signalling or CD40. For T lymphocytes IL-4 has also a crucial role in transcriptional regulation of CB1. In lymphocytes, cannabinoid act in several ways – by affecting cell migration, cytokine response, at high doses inhibit cell proliferation and inducing cell death. The possible role for the endocannabinoid system in the immune microenvironment of lymphoma is discussed.
31) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278325/
Wasik AM, Nygren L, Almestrand S, et al. Perturbations of the endocannabinoid system in mantle cell lymphoma: correlations to clinical and pathological features. Oncoscience. 2014;1(8):550-557.
32) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171598/
Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget. 2014;5(15):5852-5872.
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NICE IMAGE OF GREEN STAIN FOR CB1 RECEPTOR
33) http://www.nature.com/leu/journal/v17/n9/full/2403057a.html
Leukemia (2003) 17, 1880–1890. doi:10.1038/sj.leu.2403057
High level of cannabinoid receptor 1, absence of regulator of G protein signalling 13 and differential expression of Cyclin D1 in mantle cell lymphoma
T C Islam1, A C Asplund1, J M Lindvall1, L Nygren2, J Liden3, E Kimby4, B Christensson2, C I E Smith1 and B Sander2
34) full pdf  https://www.researchgate.net/profile/Eva_Kimby2/publication/7432907_Cannabinoid_receptor_ligands_mediate_growth_inhibition_and_cell_death_in_mantle_cell_lymphoma/links/02e7e52bae47431e6b000000.pdf
http://febsletters.org.marlin-prod.literatumonline.com/article/S0014-5793(05)01380-3/abstract
Flygare, Jenny, et al. “Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.” FEBS letters 579.30 (2005): 6885-6889.
We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma. In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected. Interestingly, equipotent doses of the CB1 antagonist SR141716A and the CB1/CB2 agonist anandamide inflicted additive negative effects on viability. Moreover, treatment with the CB1/CB2 agonist Win-55,212-2 caused a decrease in long-term growth of MCL cells in culture. Induction of apoptosis, as measured by FACS/Annexin V–FITC, contributed to the growth suppressive effect of Win-55,212-2. Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.
35) http://molpharm.aspetjournals.org/content/70/5/1612.long
Gustafsson, Kristin, et al. “Cannabinoid receptor-mediated apoptosis induced by R (+)-methanandamide and Win55, 212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma.” Molecular pharmacology 70.5 (2006): 1612-1620.
36)  Int J Cancer. 2008 Sep 1;123(5):1025-33.
Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.
Gustafsson K1, Wang X, Severa D, Eriksson M, Kimby E, Merup M, Christensson B, Flygare J, Sander B.
Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type (n = 62). A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue. With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. Low levels of the splice variant CB1a, previously shown to have a different affinity for cannabinoids than CB1, were detected in 44% of the lymphomas, while CB1b expression was not detected. In functional studies using MCL, Burkitt lymphoma (BL), chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog R(+)-methanandamide (R(+)-MA) induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL. In vivo treatment with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human MCL. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.
37) Gustafsson, Kristin, et al. “Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism.” Molecular Cancer Research 7.7 (2009): 1086-1098.
Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids. Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA). We further interfered with the conversion of ceramide into sphingolipids that promote cell growth. Treatment with R-MA led to increased levels of ceramide species C16, C18, C24, and C24:1 and transcriptional induction of ceramide synthases (CerS) 3 and 6. The effects were attenuated using SR141716A, which has high affinity to cannabinoid receptor 1 (CB1). The CB1-mediated induction of CerS3 and CerS6 mRNA was confirmed using Win-55,212-2. Simultaneous silencing of CerS3 and CerS6 using small interfering RNA abrogated the R-MA-induced accumulation of C16 and C24. Inhibition of either of the enzymes serine palmitoyl transferase, CerS, and dihydroceramide desaturase within the de novo ceramide pathway reversed ceramide accumulation and cell death induced by R-MA treatment. To enhance the cytotoxic effect R-MA, sphingosine kinase-1 and glucosylceramide synthase, enzymes that convert ceramide to the pro-proliferative sphingolipids sphingosine-1-phospate and glucosylceramide, respectively, were inhibited. Suppression of either enzyme using inhibitors or small interfering RNA potentiated the decreased viability, induction of cell death, and ceramide accumulation induced by R-MA treatment. Our findings suggest that R-MA induces cell death in MCL via CB1-mediated up-regulation of the de novo ceramide synthesis pathway. Furthermore, this is the first study were the cytotoxic effect of a cannabinoid is enhanced by modulation of ceramide metabolism. (Mol Cancer Res 2009;7(7):1086–98)
38) Wasik, A. M., et al. “WIN55, 212-2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells.” Cell death & disease 2.11 (2011): e225.
Cannabinoid receptors 1 (CB1) and/or 2 (CB2) are overexpressed in many types of human malignancies including mantle cell lymphoma (MCL). Agonists to CB1 and CB2 promote ceramide de novo synthesis, p38–mitogen-activated protein kinase-dependent activation of caspase-3 and apoptotic cell death in most MCLs. However, in this report we describe that in some MCLs the response to treatment with cannabinoids decreased cell viability as assessed by metabolic activity but did not involve the caspase-3 cascade or loss of plasma membrane integrity. Both primary cells from one MCL patient and the MCL cell line Granta519 responded to treatment with cannabinoids by formation of cycloheximide-sensitive cytoplasmic vacuoles, but did not enter apoptosis. The persistent expression of mammalian homolog of Atg8 with microtubule-associated protein-1 light chain-3 II (LC3 II) and p62, as well as the lack of protection from chloroquine, indicates that lysosomal degradation is not involved in this cytoplasmic vacuolation process, distinguishing from classical autophagy. Transmission electron microscopy images and immunofluorescence staining of endoplasmic reticulum (ER) chaperone calreticulin showed that the vacuoles were of ER origin and that chromatin remained normal. These features resemble paraptosis-like cell death—a third type of a programmed cell death not previously described in response to cannabinoids.
Sulfazalazine
39) Ishimoto, Takatsugu, et al. “CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth.” Cancer cell 19.3 (2011): 387-400.  CD44 regulates redox status in cancer cells by stabilizing xCT Cancer cell 2011 Ishimoto Takatsugu  The xCT Inhibitor Sulfasalazine Suppresses CD44-Dependent Tumor Growth and Promotes Activation of p38MAPK in Tumor Cells In Vivo –  Stem Cells !!!
40) Lewerenz, Jan, et al. “The cystine/glutamate antiporter system xc− in health and disease: from molecular mechanisms to novel therapeutic opportunities.” Antioxidants & redox signaling 18.5 (2013): 522-555.  The cystine glutamate antiporter system xc in health and disease Lewerenz Jan 2013

Early evidence suggested that nonsteroidal anti-inflammatory drugs also inhibit system xc – (15). On this basis, the Gout lab identified the FDA-approved drug sulfasalazine, commonly used to treat chronic inflammatory diseases such as rheumatoid arthritis, as a potent system xc – inhibitor (79). However, this compound is also a potent inhibitor of nuclear factor kappa B (NF-jB) activation (283).
41) Gout, P. W., et al. “Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x c-cystine transporter: a new action for an old drug.” Leukemia (08876924) 15.10 (2001).  1Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada
42) Doxsee, Daniel W., et al. “Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy.” The Prostate 67.2 (2007): 162-171.
43) Chung, W. Joon, and Harald Sontheimer. “Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor‐κB.” Journal of neurochemistry 110.1 (2009): 182-193.
44) Guan, Jun, et al. “The x c− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine.” Cancer chemotherapy and pharmacology 64.3 (2009): 463-472.
45) Dixon, Scott J., et al. “Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis.” Elife 3 (2014): e02523.Pharmacological inhibition of cystine glutamate exchange induces endoplasmic reticulum stress and ferroptosis.Elife 2014 Dixon SCott
46) Narang, Vishal S., et al. “Sulfasalazine-induced reduction of glutathione levels in breast cancer cells: enhancement of growth-inhibitory activity of doxorubicin.” Chemotherapy 53.3 (2007): 210-217. Sulfasalazine induced reduction of glutathione levels in breast cancer cells Narang 2007 Chemotherapy
Background: We previously showed that the anti-inflammatory drug, sulfasalazine (salicylazosulfapyridine, SASP), can arrest proliferation of MCF-7 and MDA-MB-231 mammary cancer cells by inhibiting uptake of cystine via the xc– cystine/glutamate antiporter. Here we examined SASP with regard to reduction of cellular glutathione (GSH) levels and drug efficacy-enhancing ability. Methods: GSH levels were measured spectrophotometrically. Cellular drug retention was determined with 3H-labeled methotrexate, and drug efficacy with a colony formation assay. Results: Incubation of the mammary cancer cells with SASP (0.3–0.5 mM) led to reduction of their GSH content in a time- and concentration-dependent manner. Similar to MK-571, a multidrug resistance-associated protein inhibitor, SASP increased intracellular accumulation of methotrexate. Preincubation of cells with SASP (0.3 mM) significantly enhanced the potency of the anticancer agent doxorubicin (2.5 nM). Conclusions: SASP-induced reduction of cellular GSH levels can lead to growth arrest of mammary cancer cells and enhancement of anticancer drug efficacy.
We also showed, for the first time, that sulfasalazine (salicylazosulfapyridine, SASP), an anti-inflammatory drug used against inflammatory bowel disease
and rheumatoid arthritis, is a potent inhibitor of x c – – mediated cystine uptake [16] , and that it can markedly inhibit proliferation of human breast carcinoma cells at relatively low concentrations (0.2–0.5 m M ) via cystine starvation [17] .
The human breast carcinoma cell lines, MCF-7 (estrogen receptor positive) and MDA-MB-231 (estrogen receptor negative, highly invasive),
From Rheumatoid artritis.net:  How is sulfasalazine taken?
Sulfasalazine comes in a 500-mg tablet for oral administration and it typically started at a dose of 500 mg per day and increased by 500 mg every week, while monitoring for side effects, until a daily target dose (this is determined by your weight, approximately 40 mg/kg) is reached. For most adult patients with RA, the final daily dose ranges from 2000-3000 mg (2-3 grams). If gastrointestinal (GI) side effects are problematic, divided doses can be used or a special enteric-coated form (Azulfidine EN-tabs) to protect against GI effects. To help prevent stomach upset, you should take sulfasalazine with food, followed by a full glass of water.1,2
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Chloroquin synergistic with Artemisinin ?

47) Ganguli, Arnab, et al. “Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis.” Biochimie 107 (2014): 338-349.  Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis Ganguli Biochimie 2014

The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART.
However, the low toxicity and low bio-availability make it unsuitable for use as an anticancer agent. Works are going on to try to increase the potency of artemisinin and make it acceptable as an anticancer drug.
One of the well known late phase autophagy inhibitor is chloroquine (CQ). For more than six decades CQ has been using to treat several diseases (like, malaria, rheumatoid arthritis, lupus) because of its high effectiveness and well tolerated by human [23]
Chloroquin, its protonated forms are trapped within the acidic vacuoles (late endosome and lysosome), causing increased in pH, inactive lysosomal hydrolysates, thus increase the autolysosomes accumulation by inhibiting
the autophagy.
For pretreatment regime, we treated A549 cells (lung cancer) with 25-100 μM CQ for 12 h and subsequently after washing the cells, treatment with 75 μM ART for 72 h was performed.
For co-treatment, we used 75 μM ART and different concentration of CQ (2.5-25 μM) simultaneously to treat A549 cells for 72 h. In both the cases, we measured cell viability by MTT assay and calculated combination index (CI) (Fig 5A-D). We found that CI value of pre-treatment (Fig. 5A and C) were much more lower than CI values of co-treatment (Fig.5 B and D), indicating pre-treatment had synergistic effect where as co-treatment had nearly an additive effect.
Furthermore co-treatment also reduced cell viability of normal cells (Fig. 5E) but pretreatment did not have any cytotoxic effect towards normal cells (Fig. 5F).
In control experiments, when cells were treated with separately CQ (50
μM for 12 h) and ART (75 μM for 72 h), and the apoptotic populations were 3% and 16%  respectively, but in case of combination treatment, apoptotic population was increased to 40% (Fig. 6C).
We observed that NAC significantly reduced AVOs in both single and double treated A549 cells (Fig. 8C). Furthermore, scavenging ROS by NAC decreased the cleaved caspase 3 expression (Fig. 8E) and subsequently blocked apoptotic cells death (Fig. 8D)
pretreatment  of CQ was found to be more effective to increase the potency of artemisinin than co-treatment (Fig.5A-E).
48) Solomon, V. Raja, and Hoyun Lee. “Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.” European journal of pharmacology 625.1 (2009): 220-233. Chloroquine and its analogs a new promise of an old drug for effective and safe cancer therapies Solomon Raja Hoyun Lee European journal of pharmacology 2009
49) Kimura, Tomonori, et al. “Chloroquine in cancer therapy: a double-edged sword of autophagy.” Cancer research 73.1 (2013): 3-7.
The dosage of chloroquine usually ranges between 100 and 500 mg/day. Side effects are minimal at low doses, while many more toxic effects occur at higher doses, such as visual disturbances, gastrointestinal upset, electrocardiographic changes, headache, and pruritus.
50) Eur J Pharmacol. 2016 Jan 15;771:139-44.  Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies. Pascolo S1.
Chloroquine, a drug used for over 80 years to treat and prevent malaria and, more recently, to treat autoimmune diseases, is very safe but has a plethora of dose-dependent effects. By increasing pH in acidic compartments it inhibits for example lysosomal enzymes. In the context of cancer, Chloroquine was found to have direct effects on different types of malignancies that could potentiate chemotherapies. For example, the anti-malaria drug may inhibit both the multidrug-resistance pump and autophagy (mechanisms that tumor cells may use to resist chemotherapies), intercalate in DNA and enhance the penetration of chemotherapeutic drugs in cells or solid cancer tissues. However, these activities were mostly demonstrated at high doses of Chloroquine (higher than 10mg/kg or 10mg/l i.e. ca. 31μM). Nevertheless, it was reported that daily uptake of clinically acceptable doses (less than 10mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the survival of glioblastoma patients (Sotelo et al., 2006; Briceno et al., 2007). However, the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined. The present article reviews the several known direct and indirect effects of different doses of Chloroquine on cancer and how those effects may indicate that a fine tuning of the dose/schedule of Chloroquine administration versus chemotherapy may be critical to obtain an adjuvant effect of Chloroquine in anti-cancer treatments. We anticipate that the appropriate (time and dose) addition of Chloroquine to the standard of care may greatly and safely potentiate current anti-cancer treatments.
51)  Sukhai, Mahadeo A., et al. “Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” Journal of Clinical Investigation 123.1 (2013): 315.
mefloquin and artemisinin combination
However, strikingly, 10 of these, including the artemisinin class of antimalarials (27, 28), proved to be compounds that are known to increase the production of ROS.
Synergistic combinations of mefloquine and artenimol or artesunate also synergistically increased ROS production
mefloquine specifically targets lysosomal function. This finding is consistent with mefloquine’s known ability to preferentially accumulate in lysosomes of the malarial parasite
Mefloquine directly disrupted lysosomes isolated from AML cell lines and primary AML patients’ samples, in a dose-dependent manner, as measured by release of cathepsins B and L
The effects of mefloquine were specific to lysosomes, as mefloquine treatment did not disrupt isolated mitochondria
In a dose-dependent manner, mefloquine disrupted lysosomes in TEX leukemia cells and mefloquine-sensitive cells from AML patients, but not normal hematopoietic cells
Taken together, these data point to mefloquine-mediated lysosomal disruption as the cellular mechanism underlying antileukemic action.
AML cells have increased lysosomal mass compared with normal hematopoietic cells.
TEM revealed that lysosomes are larger in primary human AML cells, including the CD34+ AML cells, as well as in AML cell lines, in comparison to the lysosomes found in normal human CD34+ hematopoietic cells
Here we report that mefloquine, a quinoline approved for the treatment and prevention of malaria (23, 24), has toxicity for human AML cells including AML progenitors, while sparing normal human hematopoietic cells treated with the same doses.
serum concentrations of mefloquine up to 5 μM have been reported in individuals receiving 250 mg weekly for malaria prophylaxis (59, 60). Thus, antileukemia concentrations of mefloquine may be pharmacologically achievable.
The antimalarial chloroquine is structurally similar to mefloquine and inhibits the degradation of autophagy targets in the autophagolysosome. Through this mechanism, chloroquine can induce cell death and sensitize cells to chemotherapy (including imatinib mesylate in chronic myeloid leukemia; refs. 63–66) and radiation. However, as it involves induction of lysosome disruption, the mechanism of action of mefloquine appears distinct from that of chloroquine and other inhibitors of autophagy.
52) Neuro Oncol. 2010 May;12(5):473-81.  Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent.
Geng Y1, Kohli L, Klocke BJ, Roth KA.
Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.
What is the usual dose of Chloroquine?  From rheuminfo.com

Chloroquine is available in 250 mg tablets. The dose is based on your lean body weight with the standard dose ranging from one-half (125 mg) to one tablet (250 mg) per day. The dose should be no more than 3 mg/kg/day of lean body weight.
Why do I need to see an Ophthalmologist (Eye Doctor) when I am taking Chloroquine?
As mentioned above, Chloroquine can cause damage to the back of the eye (retina). Early eye toxicity is not usually a serious problem. However, once serious damage occurs, it is permanent. Therefore, appropriate monitoring of the eye by a medical specialist familiar with the side-effects of Chloroquine is essential. The eye examination includes regular tests such as vision and eye pressure. It also includes tests which are not part of a regular eye check-up such as testing for colour vision and testing your visual fields. Your doctor will usually ask you to see an ophthalmologist every 6-24 months.
Ferroptostis
53)  Xie, Y., et al. “Ferroptosis: process and function.” Cell Death & Differentiation (2016).
56) Nandakumar, Dalavaikodihalli Nanjaiah, et al. “Curcumin-artemisinin combination therapy for malaria.” Antimicrobial agents and chemotherapy 50.5 (2006): 1859-1860.
Synergy with allicin full pdf
57) .Synergistic Anticancer Effect of Artesunate with Allicin in Osteosarcoma Jiang_2013 Asian Pac J Cancer Prev. 2013;14(8):4615-9
The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo.  Jiang W1, Huang Y, Wang JP, Yu XY, Zhang LY.
Artesunate, extracted from Artemisia annua, has been proven to have anti-cancer potential. Allicin, diallyl thiosulfinate, the main biologically active compound derived from garlic, is also of interest in cancer treatment research. This object of this report was to document synergistic effects of artesunate combined with allicin on osteosarcoma cell lines in vitro and in vivo.
METHODS:After treatment with artesunate and allicin at various concentrations, the viability of osteosarcoma cells was analyzed by MTT method, with assessment of invasion and motility, colony formation and apoptosis. Western Blotting was performed to determine the expression of caspase-3/9, and activity was also detected after drug treatment. Moreover, in a nude mouse model established with orthotopic xenograft tumors, tumor weight and volume were monitored after drug administration via the intraperitoneal (i.p.) route.
RESULTS:The viability of osteosarcoma cells in the combination group was significantly decreased in a concentration and time dependent manner; moreover, invasion, motility and colony formation ability were significantly suppressed and the apoptotic rate was significantly increased through caspase-3/9 expression and activity enhancement in the combination group. Furthermore, suppression of tumor growth was evident in vivo.
CONCLUSION:Our results indicated that artesunate and allicin in combination exert synergistic effects on osteosarcoma cell proliferation and apoptosis.
synergy with resveratrol
58) J Cancer Res Clin Oncol. 2014 Dec;140(12):2065-75.
Synergic effects of artemisinin and resveratrol in cancer cells.
Li P1, Yang S, Dou M, Chen Y, Zhang J, Zhao X.
The aim of this study was to investigate whether resveratrol (Res) combined with artemisinin (ART) possess synergistic effect on different cancer cells.
MATERIALS AND METHODS:The viability of HepG2 and HeLa cells treated with ART and Res was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Combination index (CI) analysis and isobologram were used to assess the synergistic effect of ART and Res in different ratios. Wound-healing assay was used to investigate the migration rate. AO staining and fluorescent microscopy measurements were performed to detect the cell apoptosis. Reactive oxygen species (ROS) was measured with 2’7′-dichlorofluorescein diacetate (DCFH-DA).
RESULTS:MTT assay indicated that ART and Res inhibited the growth of HeLa and HepG2 cells in a dose-dependent manner. The combination of ART and Res exhibited the strongest anticancer effect at the ratio of 1:2 (ART to Res). The combination of the two drugs also markedly reduced the ability of cell migration. Apoptosis analysis showed that combination of ART and Res significantly increased the apoptosis and necrosis rather than use singly. Additionally, ROS levels were elevated by combining ART with Res.
CONCLUSIONS:Taken together, the present study suggested that ART and Res possessed the synergistic anti-tumor effect. ART in combination with Res could be an effective therapeutic strategy for cancer.
59) Tolomeo,M. et al. (2005) Pterostilbene and 3-hydroxypterostilbene are effective apoptosis-inducingagents in MDR and BCR-ABL-expressing leukemia cells. Int. J. Biochem. Cell Biol. 37, 1709–1726 Pterostilbene apoptosis in MDR leukemia cells Tolomeo 2005
Gleditsia sinensis
60)  Oncol Rep. 2003 Sep-Oct;10(5):1601-7.
Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia.  Chow LM1, Chui CH, Tang JC, Teo IT, Lau FY, Cheng GY, Wong RS, Leung TW, Lai KB, Yau MY, Gou D, Chan AS.
The anti-leukemia activity of the saponin rich Gleditsia sinensis Lam. fruit extract (GSE) was investigated on cancer cell lines and bone marrow cells obtained from consented patients with chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) during presentation. The growth inhibitory activity of the extract was determined by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay. Colony formation assay was performed to investigate the regeneration potential. Cellular morphology change was studied. Apoptosis was demonstrated by DNA electrophoresis, reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The mean concentration to inhibit the cell growth by 50% (MTS50) was 18+/-1.6 micro g/ml for K562 CML cell line and 12+/-1.3 micro g/ml for HL-60 acute promyelocytic leukemia cell line. Patient samples showed a mean MTS50 of 13-28 micro g/ml. Non-malignant hematological disorder bone marrow samples showed a mean MTS50 from 45 to 53 micro g/ml. Loss of regeneration property after treatment with GSE of these two cancer cell lines were confirmed by colony formation assay. GSE was able to induce cell shrinkage in K-562. DNA laddering was observed by incubating the leukemia cells with GSE. RT-PCR demonstrated that the pro-apoptic gene bax was induced while the anti-apoptic gene bcl-2 and cell cycle active gene PCNA were reduced. Flow cytometric analysis showed that the apoptotic effect of GSE on leukemia cell line was time- and dose-dependent. Thus GSE might be potentially used as a chemotherapeutic drug to treat patients with acute and chronic myelogenous leukemia.
61) Int J Mol Med. 2005 Mar;15(3):539-43.
Gleditsia sinensis fruit extract-induced apoptosis involves changes of reactive oxygen species level, mitochondrial membrane depolarization and caspase 3 activation.  Chui CH1, Lau FY, Chan AS, Cheng GY, Wong RS, Lai KB, Kok SH, Yeung TT, Teo IT, Yau MY, Cheung F, Cheng CH, Tang JC.
Recently, we have shown that the anomalous fruit extract of Gleditsia sinensis (GSE) processes apoptotic activity on numerous solid tumour and leukaemia cell lines as well as primary cultured leukaemia cells obtained from bone marrow aspirate of patients. GSE treated cancer cells exhibited apoptotic features as readily illustrated by morphological investigation, DNA fragmentation analysis and TUNEL labelling methods. Elevation of intracellular superoxide dismutase activity was observed. However, the detailed mechanism still remains undefined. Here we further demonstrated that cell cycle arrest, increment of hydrogen peroxide production, changes of intracellular acid-base equilibrium and mitochondrial membrane potential depolarization (DeltaPsi(m)) were induced from cancer cells after GSE incubation. Caspase 3 protease activity was significantly enhanced upon GSE treatment. Taken together, a defined signaling pathway for the mechanistic action of GSE on cancer cells was worked out.
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Ivermectin
62) Sharmeen, Sumaiya, et al. “The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.” Blood 116.18 (2010): 3593-3603.
To identify known drugs with previously unrecognized anticancer activity, we compiled and screened a library of such compounds to identify agents cytotoxic to leukemia cells. From these screens, we identified ivermectin, a derivative of avermectin B1 that is licensed for the treatment of the parasitic infections, strongyloidiasis and onchocerciasis, but is also effective against other worm infestations. As a potential antileukemic agent, ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. Ivermectin also delayed tumor growth in 3 independent mouse models of leukemia at concentrations that appear pharmacologically achievable. As an antiparasitic, ivermectin binds and activates chloride ion channels in nematodes, so we tested the effects of ivermectin on chloride flux in leukemia cells. Ivermectin increased intracellular chloride ion concentrations and cell size in leukemia cells. Chloride influx was accompanied by plasma membrane hyperpolarization, but did not change mitochondrial membrane potential. Ivermectin also increased reactive oxygen species generation that was functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with cytarabine and daunorubicin that also increase reactive oxygen species production. Thus, given its known toxicology and pharmacology, ivermectin could be rapidly advanced into clinical trial for leukemia.
63)  Draganov, Dobrin, et al. “Modulation of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).
64) Furusawa, Shinobu, et al. “Potentiation of Doxorubicin‐Induced Apoptosis of Resistant Mouse Leukaemia Cells by Ivermectin.” Pharmacy and Pharmacology Communications 6.3 (2000): 129-134.
65) Melotti, Alice, et al. “The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.
Patent – Ivermectin used with chemotherapy for lymphoma
66) Use of synergistic combinations of an avermectin and an antineoplastic compounds for the treatment of hematological malignancies
EP 2498785 A1 (text from WO2011054103A1)
The disclosure relates to a method of treating a hematological malignancy comprising administering to a subject in need thereof a synergistic combination of a first compound comprising an effective amount of one or more Avermectins and a second compound comprising a chemotherapeutic, preferably daunorubicin, cyarabine, doxorubicin, idarubicin mitoxantrone, amsacrine, and mixtures thereof
67) FURUSAWA SHINOBU ET AL: “Potentiation of doxorubicin-induced apoptosis of resistant mouse leukaemia cells by ivermectin”, PHARMACY AND PHARMACOLOGY COMMUNICATIONS, vol. 6, no. 3, March 2000 (2000-03), pages 129-134, XP9167795, ISSN: 1460-8081
68) YURI N. KORYSTOV ET AL: “Avermectins inhibit multidrug resistance of tumor cells”, EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 493, no. 1-3, 1 June 2004 (2004-06-01), pages 57-64, XP055055776, ISSN: 0014-2999,
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Diclofenac
69) The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status.  Hesham M. Hassan1, Michelle L. Varney2, Aalia M. Aly3, Shantaram S. Joshi2, Rakesh K. Singh2, and Bhavana J. Dave2
Author Affiliations 1Assiut University, Assiut, Egypt;
2university of Nebraska Medical Center, Omaha, NE;
3South Egypt Cancer institute, Assiut, Egypt.
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA
Abstract Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapses and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome in MCL. Diclofenac has been reported to increase p53 pathway activity, upregulates p73 expression and inhibit cell growth; hence we investigated the ability of diclofenac to induce apoptosis and/or cell cycle arrest in MCL, and its dependence on p53 status. To investigate the response of MCL to diclofenac, wild-type p53 [Granta-519 and JVM-2] and mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines and primary human cells isolated from MCL patients were used. Cell proliferation, apopotosis, and expression of down-stream signaling p53 targets were analyzed. Nontoxic concentrations of diclofenac induced concentration- and duration-dependent inhibition of MCL cell growth independent of p53 status. Diclofenac treatment also resulted in cell cycle arrest and cell death. Molecularly, diclofenac treatment was associated with increased activity of caspases 3, 7, and 8. Increased p53 pathway activity was demonstrated by duration-dependent induction of p53 transcriptional target genes, including the cell cycle regulatory molecule p21 and pro-apoptotic molecules including, PUMA, NOXA, BIM, and CD95. Most importantly, diclofenac treatment was associated with enhanced expression of the pro-apoptotic isoforms of the p53 homologue TAp73. Our data demonstrates that diclofenac treatment results in decreased cell cycle progression, and increased apoptosis that is associated with increased p53 pathway activity, independent of p53 status, and increased activity of its family member p73.
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Crowd Funding
70) Can Artesunate, an antimalarial drug, provide an effective and affordable treatment for Bowel Cancer  ? By Professor Sanjeev Krishna
(71) Krishna, Sanjeev, et al. “A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer.” EBioMedicine 2.1 (2015): 82-90.
This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site Colo-rectal Cancer (CRC) were randomised (n = 23)  to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11).
During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC.  Till this analysis, there have been no deaths in artesunate recipients (despite some patients having relatively poor prognosis), and 3 deaths in placebo recipients.
Animal Study – Veterinary Medicine  Whole leaf extract 30:1 artemesia

72) Breuer, Elmar, and Thomas Efferth. “Treatment of iron-loaded veterinary sarcoma by Artemisia annua.” Natural products and bioprospecting 4.2 (2014): 113-118.
Veterinary Clinic for Pets, Müllheim/Baden, Germany Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany
1:30 A.annua extract for the treatment of spontaneous tumors and dogs and cats
This indicates that adjuvant iron-triggered A.annua impacts the overall survival rates of dogs suffering from sarcoma and improves the treatment success over that of surgery alone.
An interesting result was that artemisinin represented only a minor constituent in A.annua and that scopoletin was the most abundant phytochemical. It is well known that A.annua contains a large panel of different secondary metabolites, including scopoletin, which are cytotoxic [5, 57, 76–79]. The activity of the A.annua preparation in pet tumors and the presence of large amounts of scopoletin raise the question of whether scopoletin might contribute to the anticancer effect of this plant rather than artemisinin. The in vitro cytotoxicity of scopoletin towards cancer cells has been previously described [80–82].
Verterinary Artemsinin
73) LupArte – Artemisia Annua Extrakt 30:1
Einzelfuttermittel mit Zusatzstoff für Hunde und Katzen
pro 450 mg- Kapsel: Aromastoff 450 mg konzentrierten Artemisia Annua Pulverextrakt (30:1), prebiotisches Inulin aus Artischockenherzen (50 mg)
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Targeting progenitor cells   Parthenolide (Feverfew)
74) Guzman, Monica L., et al. “The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.” Blood 105.11 (2005): 4163-4169.  Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor κ B (NF-κB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
Parthenolide (PTL) is a sesquiterpene lactone found as the major active component in Feverfew (Tanacetum parthenium), an herbal medicine that has been used to treat migraine and rheumatoid arthritis for centuries.12 More recently, PTL has been found to have several other properties, including antitumor activity, inhibition of DNA synthesis, and inhibition of cell proliferation in different cancer cell lines.13-16 In addition, PTL sensitizes cancer cells to other antitumor agents17-20 and acts as a chemopreventive agent in a UVB-induced skin cancer animal model.21 PTL is a potent inhibitor of NF-κB activation and has been shown to directly bind IκB-kinase (IKK)22,23 and to modify the p50 and p65 NF-κB subunits.24,25 PTL can also block signal transducers and activators of transcription 3 (STAT3) phosphorylation on Tyr705,26 sustain c-Jun N-terminal kinase (JNK) activation,17,18 and increase intracellular reactive oxygen species (ROS).13,27
Targeting cancer stem cells
75)
Naujokat, Cord, and Roman Steinhart. “Salinomycin as a Drug for Targeting Human Cancer Stem Cells.” Journal of Biomedicine and Biotechnology 2012 (2012).
In particular, the biomolecules salinomycin and parthenolide as well as the biguanide metformin have been demonstrated to induce apoptosis in various types of human cancer cells [108, 123, 124], suggesting that these compounds may contribute to the eradication of cancer more effectively than compounds targeting either CSCs or regular cancer cells. Moreover, the ionophore antibiotic salinomycin seems to have even extended capabilities of eliminating cancer (Table 1), because this compound has been demonstrated to effectively target regular cancer cells [16, 125–127], highly multidrug and apoptosis-resistant cancer cells [16, 85, 125], and CSCs [16, 84, 87, 88, 128–131].
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synergy artemisinin with butyrate
76) Anticancer Res. 2005 Nov-Dec;25(6B):4325-31.
Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.Singh NP1, Lai HC.  Butyric acid is a short chain fatty acid produced by large bowel bacterial flora. It serves as an antiinflammatory agent and nutrient for normal colon cells. Butyric acid has also been shown to induce apoptosis in colon and many other cancer cells. Artemisinin is a compound extracted from the wormwood Artemisia annua L. It has been shown to selectively kill cancer cells in vitro and to be effective in treating animal and human cancer. We and others have found that the artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by apoptosis. In the present study, the efficacy of a combined treatment of DHA and butyric acid at low doses in killing cancer cells was investigated.
MATERIALS AND METHODS:Molt-4 cells (a human lymphoblastoid leukemia cell line) and freshly isolated human lymphocytes, cultured in complete RPMI-1640 medium, were first incubated with 12 microM of human holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one hour to enhance the iron concentration in the cells. Cells from each cell type were then divided into 20 flasks. These flasks were grouped into four sets of five cultures each. Zero, 5, 10 or 20 microM of DHA was added, respectively, to these sets and the cells were incubated at 37 degrees C for one hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate was then added to the five cultures of each set, respectively. Thus, the treatments involved a combination of 4 doses of DHA and 5 doses of sodium butyrate. The cells were counted immediately before the addition of DHA, and at 24 and 48 hours after the addition of sodium butyrate.
RESULTS:DHA alone at the 24-hour time-point and 20 microM concentration significantly reduced the number of Molt-4 cells in the culture by approximately 40% (p < 0.001, compared to non-treated control), whereas it did not significantly affect the number of normal human lymphocytes. Similarly, 1 mM sodium butyrate alone at 24 hours reduced the number of Molt-4 cells by approximately 32% (p < 0.001, compared to non-treated control), without significantly affecting normal human lymphocytes. The combination of 20 microM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes.
CONCLUSION:DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy.
The oral intake of artemisinin and its analogs (7, 43) and butyric acid (44) is safe. Oral administration of the artemisinin analogs, artesunate (100 mg in a healthy adult) resulted in micromolar plasma concentration of DHA (45). The basal plasma concentration of butyric acid is normally >1 ÌM (42). Oral or intravenous administration of sodium butyrate (50 mg/kg) has been shown to increase the plasma butyrate concentration to the millimolar range in rats (46).
The artemisinin-butyrate combination may work well, particularly for colon cancer where butyrate concentrations can be raised by simple oral probiotic intake of butyric acid producing Lactobacilli.
Artemisinin Synergy with Rituximab anti-CD-20 Ab
77) Sieber, Sebastian, et al. “Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate.” International journal of oncology 35.1 (2009): 149-158.  Combination treatment of malignant B cells Rituximab and Artesunate Sieber Sebastian Int j oncology 2009

Chemotherapy of non-Hodgkin’s lymphoma is frequently hampered by drug resistance. The monoclonal antibody rituximab specifically targets the CD20 antigen and sensitizes B-cell lymphoma cells to standard anticancer drugs. In the present investigation, we analyzed, whether a combination of rituximab and artesunate may act in a complementary manner and eventually synergize in tumor cell killing. Artesunate is an anti-malarial drug, which also exerts profound activity towards cancer cells. While rituximab alone was minimally cytotoxic, rituximab increased cytotoxicity to artesunate in Ramos cells. Artesunate induced apoptosis, induced Fas/CD95 expression and the formation of reactive oxygen species (ROS) and resulted in a breakdown of mitochondrial membrane potential. This argues for the involvement of both receptor-driven extrinsic and mitochondrial intrinsic routes of apoptosis. Rituximab increased Fas/CD95 expression and ROS formation and decreased mitochondrial membrane potential ultimately leading to increased apoptosis induced by artesunate. The transcription factors YY1 and Sp1 are upstream regulators of apoptosis by controlling the expression of apoptosis-regulating genes. YY1 and Sp1 were down-regulated and Fas/CD95 was up-regulated by rituximab and artesunate indicating that artesunate activated the Fas/CD95 pathway and that rituximab increased the susceptibility of tumor cells to artesunate-induced apoptosis. Furthermore, rituximab affected the expression of antioxidant genes. The antibody decreased artesunate-induced up-regulation of catalase expression and increased artesunate-induced down-regulation of glutathione S-transferase-phi expression. Manganese-dependent superoxide dismutase expression was not changed by artesunate. Antioxidant proteins may help to detoxify artesunate-induced ROS. Rituximab reversed the artesunate-induced expression changes of antioxidant genes and, hence, reduced the detoxification capacity of Ramos cells. The effects of rituximab on antioxidant genes represent a novel mechanism of rituximab for chemosensitization.
Lymphoma and Myeloma Highly Sensitive to Artemisinin
78) Eur J Haematol. 2013 Oct;91(4):339-46.  Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate.
Holien T1, Olsen OE, Misund K, Hella H, Waage A, Rø TB, Sundan A.
The use of new drugs has improved the treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Nevertheless, over time many patients relapse and develop resistance to treatment, and efforts are needed to overcome drug resistance. The widely used malaria drug artesunate has been reported to have antitumor activity, and we aimed to test the effects of artesunate on a panel of myeloma and lymphoma cells.
METHODS:Myeloma and DLBCL cell lines were treated with artesunate in vitro. The effects of artesunate treatment were evaluated using ATP content measurements for proliferation and annexin V/propidium iodide labeling for apoptosis. Western blotting was used to look for artesunate-induced protein changes. In addition, we measured artesunate effects on patient myeloma cells in the presence of bone marrow stromal cells.
RESULTS:Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with downregulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 μm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 μm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment.
CONCLUSION:Our findings indicate that artesunate is a potential drug for treatment of multiple myeloma and DLBCL at doses of the same order as currently in use for treatment of malaria without serious adverse effects.
Use of Vitamins interacting with Artemisinin
Vitamin C, Vit D, H202 potentiates artemisinin leukemia cell death.
NOT vit E. though.

79) Anticancer Res. 2015 Apr;35(4):1867-71. Effects of antioxidants and pro-oxidants on cytotoxicity of dihydroartemisinin to Molt-4 human leukemia cells. Gerhardt T1, Jones R1, Park J1, Lu R1, Chan HW1, Fang Q1, Singh N2, Lai H1. Antioxidants and Pro oxidants cytotoxicity of dihydroartemisinin to leukemia cells Gerhardt Anticancer Res 2015
The objective of the present study was to investigate how oxidative status influences the effectiveness of cytotoxicity of artemisinin towards cancer cells. It is hypothesized that antioxidants would reduce, whereas pro-oxidants would enhance, cytotoxicity.
MATERIALS AND METHODS:Molt-4 human leukemia cells were incubated with vitamins C, E, D3, dexamethasone, or hydrogen peroxide alone or in combination with dihydroartemisinin (DHA). Concentrations of these compounds studied were similar to those achievable by oral administration. Viable cell counts were performed before (0 h) and at, 24 and 48 h after treatment.
RESULTS:Vitamin C, vitamin D3, dexamethasone, and H2O2 caused significant Molt-4 cell death. Vitamin E caused an increase in Molt-4 cell growth. Vitamin C and vitamin D3 significantly interacted with DHA at the 48-h time point and with H2O2 at both 24-h and 48-h time points.
CONCLUSION:Cellular oxidative status could alter the potency of artemisinin in killing cancer cells.
80) Hamacher-Brady, Anne, et al. “Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production.” J. Biol. Chem 2011.286 (2010): 6587-6601.  Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production J Biol Chem 2011 Hamacher Brady
We thus investigated the role of lysosomes in ART-induced PCD and determined that in MCF-7 breast cancer cells ART activates lysosome-dependent mitochondrial outer membrane permeabilization. ART impacted endolysosomal and autophagosomal compartments, inhibiting autophagosome turnover and causing perinuclear clustering of autophagosomes, early and late endosomes, and lysosomes. Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced
death, thus identifying lysosomal iron as the lethal source of reactive oxygen species upstream of mitochondrial outer membrane permeabilization
Moreover, lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling. CQ (chloroquin) resulted in enhanced vesicle size and LTR intensity, consistent with previously reported CQ-induced increase in lysosomal activities (44, 45).
The malaria parasite digests iron-rich hemoglobin in its acidic food vacuole, and the interaction of ART with hemederived iron results in lethal ROS generation (15). The parasite food vacuole is analogous to eukaryotic lysosomes, organelles that constitute a major site of intracellular degradation via hydrolytic enzymes. Therefore, we investigated the role of lysosomal iron in ART-activated ROS production and PCD in MCF-7 cells by employing the iron chelator deferoxamine mesylate (DFO). DFO specifically targets lysosomal iron as it enters the cell via endocytosis and accumulates in the lysosome (37).
In combination with ART, DFO decreased ART-triggered ROS production, with a
significant difference for ART at 20 g/ml. Moreover, at 48 h DFO significantly decreased ART-induced cell death to the levels of DFO alone at ART concentrations of both 10 and 20 g/ml.
Endolysosomal Iron Loading Enhances ART-triggered PCD
We employed diferric holotransferrin (HTF), which is actively internalized by receptor-mediated endocytosis; during transit through endolysosomes, bound iron is released due to low pH environment (18)
HTF (holotransferrin) co-treatment with both 10 and 20 g/ml ART significantly increased cell death at 24 h and at 48 h (Fig. 2C). The ensemble of findings given above indicates that lysosomal free iron serves as the major source of ROS and thereby is a critical prerequisite during ART-mediated cell death in MCF-7 breast cancer cells. In response to both ART 10 g/ml and ART 20 g/ml, AVs were clustered to the perinuclear region (Fig. 3A, arrows). DFO (iron chelator) treatment prevented AV clustering in response to ART.
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81) Yang, Nai-Di, et al. “Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin.” Journal of Biological Chemistry 289.48 (2014): 33425-33441. full free
Here, we utilized a blue fluorescence-tagged ART to investigate its localization, and our results clearly showed that ART accumulates in lysosome.
The addition of antioxidant N-acetylcysteine (NAC), which has been shown to directly react with hydrogen peroxide and superoxide (40), was able to inhibit the production of ROS induced by ART
As expected, both NAC and BAF (Baflinomycin) significantly protected ART-induced cell death (Fig. 6E).
In summary, these data indicate that lysosomal iron plays a critical role in ART-induced lysosomal activation, mitochondrial ROS production, and cell death.  These results thus indicate that ART-induced ferritin degradation is mainly performed by the lysosomes.
Altogether, these data suggest that it is not the lysosomes per se required for ART-induced cell death, but delivery and degradation of ferritin in lysosomes is required for ART-induced cell death.
First, ART accumulates in the lysosomes (Fig. 2); second, ART increases lysosomal acidification, cathepsin enzyme activity, and protein degradation via promoting lysosomal V-ATPase assembly .     At present, the exact mechanism for the lysosomal accumulation by ART is not known.  ART may increase lysosomal V-ATPase activity via promoting the assembly status of the two domains.
we believe that this perinuclear clustering of lysosomes is, in fact, an indication of autophagy induction.
the endoperoxide bridge of ART is broken by ferrous iron, and then ART becomes free radicals to target cellular organelles, such as mitochondria, and eventually leads to cell death
In fact, we also found that chloroquine inhibited the ferritin degradation and cell death induced by ART as efficiently as BAF (data not shown).
In summary, we demonstrate a novel mechanism underlying ART-induced cancer cell death. As shown in Fig. 9E, ART accumulates in lysosomes and reacts with lysosomal iron. The activated ART then promotes lysosomal function via enhancing V-ATPase assembly. One major source of iron for the cytotoxicity of ART is attained from the degradation of ferritin by lysosomes. In conclusion, we propose a new model of action on the mechanism of ART-induced cell death by focusing on lysosomal activation and ferritin degradation. At present, there is evidence demonstrating higher iron levels in cancer cells than in non-cancerous cells, and iron has been targeted for cancer therapy and prevention (69). Therefore, the results from our study support the development of this important anti-malaria drug as a cancer therapeutic agent.
82) Lai, Henry, et al. “Effects of artemisinin-tagged holotransferrin on cancer cells.” Life sciences 76.11 (2005): 1267-1279.
83) Int J Pharm. 2008 Apr 16;354(1-2):28-33. Epub 2007 Sep 6.
Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation.  Nakase I1, Lai H, Singh NP, Sasaki T.
Artemisinin and its derivatives are well known antimalaria drugs and particularly useful for the treatment of infection of Plasmodium falciparum malaria parasites resistant to traditional antimalarials. Artemisinin has an endoperoxide bridge that is activated by intraparasitic heme-iron to form free radicals, which kill malaria parasites by alkylating biomolecules. In recent years, there are many reports of anticancer activities of artemisinins both in vitro and in vivo. Artemisinins have inhibitory effects on cancer cell growth, including many drug- and radiation-resistant cancer cell lines. The cytotoxic effect of artemisinin is specific to cancer cells because most cancer cells express a high concentration of transferrin receptors on cell surface and have higher iron ion influx than normal cells via transferrin mechanism. In addition, some artemisinin analogs have been shown to have antiangiogenesis activity. Artemisinin tagged to transferrin via carbohydrate chain has also been shown to have high potency and specificity against cancer cells. The conjugation enables targeted delivery of artemisinin into cancer cells. In this review, we discuss the anticancer activities and mechanisms of action of artemisinins and the transferrin-conjugate.
mitochondrial outer membrane permeabilization (MOMP).'[
84) Lai, Henry, et al. “Artemisinin-transferrin conjugate retards growth of breast tumors in the rat.” Anticancer research 29.10 (2009): 3807-3810.  Artemisinin can retard cancer growth but not completely stop or reduce the growth. This is shown by the data of this experiment on breast cancer and on fibrosarcoma in rats reported previously by us (18). In most studies on the effect of artemisinin analogs on tumor growth in animals, an approximately 20-60% reduction in growth was generally observed in colorectal carcinoma xenografts (19), hepatoma xenograft (20), ovarian cancer (21), and HL-60 human leukemia xenograft (22). Exceptions are a study by Willoughby et al. (23) in which a complete elimination of prostate cancer xenograft in mice was reported after treatment with artemisinin, and that of Wang et al. (24) in which no significant effect on the growth of implanted Lewis lung cancer in mice was found with artemisinin treatment. Once the tumor is established, artemisinin is not very effective in reversing the progress. However, artemisinin is effective in the prevention of cancer when the target cells are still small in number.
85) Mariani, A., et al. “Iron-dependent lysosomal dysfunction mediated by a natural product hybrid.” Chemical Communications 52.7 (2016): 1358-1360.
Artesumycin is a fluorescent hybrid of the natural products marmycin A and artemisinin. It was designed to combine the lysosomotropic properties of the angucycline and the iron-reactive capacity of the endoperoxide to target the lysosomal compartment of cancer cells. Herein, we show that artesumycin inhibits cancer cell proliferation in an iron-dependent manner and chemically fragments in vitro in the presence of redox-active iron(II). Visual detection of artesumycin by fluorescence microscopy provided substantial evidence that the small molecule selectively targets lysosomes. This original approach based on a fluorescent and iron-reactive probe represents a powerful strategy for initiating and, concomitantly, visualizing lysosomal dysfunction in human cells.
(86) Yu, Zuoren, et al. “Cancer stem cells.” The international journal of biochemistry & cell biology 44.12 (2012): 2144-2151.
87) Yu, Zuoren, et al. “Cancer stem cells.” The international journal of biochemistry & cell biology 44.12 (2012): 2144-2151.
88) Pardal, Ricardo, Michael F. Clarke, and Sean J. Morrison. “APPLYING THE PRINCIPLES OF STEM-CELL BIOLOGY TO CANCER.” NATURE REVIEWS| CANCER 3 (2003): 895. APPLYING THE PRINCIPLES OF STEM-CELL BIOLOGY TO CANCER. Pardal 2003
(89) Hsieh, Hsiu-Mei, et al. “Berberine-containing pharmaceutical composition for inhibiting cancer stem cell growth or carcinoma metastasis and application thereof.” U.S. Patent Application No. 14/790,154.
90) Moselhy, J., et al. “Natural Products That Target Cancer Stem Cells.” Anticancer research 35.11 (2015): 5773.
Epigallocatechin-3-gallate (EGCG) – Green Tea
6-Gingerol – Ginger
β-Carotene – Carrot, Leafy Greens
Baicalein – Chinese Skullcap
Curcumin – Turmeric
Cyclopamine – Corn Lilly
Delphinidin – Blueberry, raspberrry
Flavonoids (Genistein) – Soy, red clover, coffee
Gossypol – Cottonseed
Guggulsterone – Commiphora (myrrh tree)
Isothiocyanates – Cruciferous vegetables
Linalool – Mint
Lycopene – Grapefruit, tomato
Parthenolide – Feverfew
Perylill alcohol – Mint, cherry, lavender
Piperine – Black pepper
Placycodon saponin – Playycodon grandifloruim
Psoralidin – Psoralea corylilyfolia
Quercetin – Capers, onion
Resveratrol – Grapes, plums, berries
Salinomycin – Streptomyces albus
Silibinin – Milk Thistle

Ursolic acid – Thyme, basil, oregano
Vitamin D3
– Fish, egg yolk, beef, cod liver oil
Withaferin A – Withania somnifera (ashwaganda)
91) Naujokat, Cord, and Roman Steinhart. “Salinomycin as a drug for targeting human cancer stem cells.” BioMed Research International 2012 (2012). Salinomycin as a drug for targeting human cancer stem cells 2012 Naujokat Cord Steinhart
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Feverfew Parthenolide
92) Ghantous, Akram, et al. “What made sesquiterpene lactones reach cancer clinical trials?.” What made sesquiterpene lactones reach cancer clinical trials Ghantous Akram 2010.  Drug discovery today 15.15 (2010): 668-678.
Medicinal plants, rich in SLs and having anti-inflammatory properties, are a potential source of NFkB inhibitors [48]. Parthenolide and artemisinin are established NF-kB inhibitors and render cancer cells sensitive to chemotherapy
[49,55]. Parthenolide was found to directly modify the NF-kB p65 subunit [58] or to suppress the activity of the upstream IkB kinase complex leading to the stabilization of the NF-kB inhibitors, IkBa and IkBb [59]. The nucleophilic attack by parthenolide occurs through a-methylene-g-lactone ring and epoxide and epoxide moieties that target specific nucleophiles but not others [60].
Parthenolide is the only small molecule, to date, that has been reported to selectively target several cancer and cancer stem cells while sparing normal counterparts [28,38,69]. NF-kB signaling is elevated in leukemic stem cells
but not in the normal hematopoietic stem cells. Parthenolide caused robust apoptosis of primary AML cells and effectively eradicated AML stem and progenitor cells in vitro without affecting hematopoietic stem cells [28,69]. The mechanism of action of parthenolide was found to be through the inhibition of NF-kB, the activation of proapoptotic p53 and an increase in reactive
oxygen species [69]. Gleevec or Cytarabine, treatments commonly used for the most aggressive leukemias, are not as effective as parthenolide because they are not as specific.
Promising antileukemic drugs should mediate cell death and inhibit leukemic stemcell- specific activity, and parthenolide fulfills these criteria
Parthenolide Phase I trial – No blood levels found ??

93) Invest New Drugs. 2004 Aug;22(3):299-305.
Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer. Curry EA 3rd1, Murry DJ, Yoder C, Fife K, Armstrong V, Nakshatri H, O’Connell M, Sweeney CJ.
Feverfew is a botanical product that contains parthenolide. Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic activity. Feverfew has been used extensively without any formal pharmacokinetic analysis. A Phase I trial was conducted to evaluate the pharmacokinetics and toxicity of parthenolide given as a component of “feverfew.”
PATIENTS AND METHODS:Feverfew (Tanacet trade mark ) was administered as a daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day was explored with subsequent dose escalations to 2, 3, and 4 mg. Assessment of plasma pharmacokinetics was performed on patients accrued to the trial. Solid phase extraction and mass spectroscopy were used to evaluate parthenolide plasma concentrations. The limit of detection for parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for response after every two cycles.
RESULTS:Feverfew given on this schedule had no significant toxicity, and the maximum tolerated dose was not reached. When parthenolide was administered at doses up to 4 mg as a daily oral capsule in the feverfew preparation, there was not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed.
CONCLUSION:Feverfew, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose- limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.
94) full pdf
GUNN, ELLEN J., et al. “The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma.” The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma Ellen Gunn 2011.  Leukemia & Lymphoma 52.6 (2011): 1085-1097.
Abstract   Multiple myeloma (MM) is an incurable plasma cell malignancy where nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor, leaving the cancer stem cells to trigger a relapse. Utilizing a three-dimensional tissue culture system where cells were grown in extracellular matrix designed  to reconstruct human bone marrow, we tested the anti-multiple myeloma cancer stem cell (MM-CSC) potential of two natural product inhibitors of nuclear factor kB (NFkB). Here we show that  parthenolide and andrographolide are potent anti-MMCSC
agents. Both natural products demonstrated preferential toxicity toward MM-CSCs over non-tumorigenic MM cells.  Addition of the bone marrow stromal compartment abrogated andrographolide activity while having no effect on
parthenolide cytoxicity. This is the first report of a natural product with anti-CSC activity in myeloma, suggesting that it has the potential to improve the survival of patients with MM by eliminating the relapse-causing MM-CSCs.
Crooks PA

95) Bioorg Med Chem Lett. 2009 Aug 1;19(15):4346-9. .
Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-kappaB inhibitor, DMAPT (LC-1). Neelakantan S1, Nasim S, Guzman ML, Jordan CT, Crooks PA.
A series of aminoparthenolide analogs (6-37) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD(50)’s in the low microM range (1.5-3.0microM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than  90% cell death at 10microM concentration against primary AML cells in culture, with LD(50) values of 1.7, 1.8 and 1.6microM.
96) Zhang, Quan, et al. “Guaianolide sesquiterpene lactones, a source to discover agents that selectively inhibit acute myelogenous leukemia stem and progenitor cells.” Journal of medicinal chemistry 55.20 (2012): 8757-8769.
97) Shanmugam, Rajasubramaniam, et al. “A water soluble parthenolide analog suppresses in vivo tumor growth of two tobacco‐associated cancers, lung and bladder cancer, by targeting NF‐κB and generating reactive oxygen species.
98) International Journal of Cancer 128.10 (2011): 2481-2494.
Karmakar, A., et al. “Nanodelivery of parthenolide using functionalized nanographene enhances its anticancer activity.” RSC advances 5.4 (2015): 2411-2420.
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full free
99) J Biol Chem. 2013 November 22; 288(47): 33542–33558.
Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells* Shanshan Pei,‡
Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells.
Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. Our findings indicate agents such as parthenolide (PTL) and piperlongumine (PLM) have a dramatic inhibitory effect on the leukemic glutathione system, whereas only a limited and transient perturbation in normal cells. This preferential effect is strongly linked to their selective toxicity toward leukemia and other cancer cell types. Importantly, we have previously shown that PTL effectively eradicates AML stem and progenitor populations (11), cells that are typically resistant/refractory to conventional chemotherapy (12, 13).
Thus, we propose that therapeutic targeting of glutathione metabolism represents a potentially powerful strategy to induce selective toxicity toward a broad range of primary leukemia cells, including malignant stem and progenitor populations.
We first studied PTL, which contains an active α,β-unsaturated-γ-lactone group (Fig. 3B, red circular area) that should readily react with the free thiol group of glutathione. Indeed, PTL induced a dose-dependent decrease of cellular glutathione within 2 h of treatment in primary AML cells
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Mantle cells have high glutathione transferase
100) Bennaceur-Griscelli, Annelise, et al. “High level of glutathione-S-transferase π expression in mantle cell lymphomas.” Clinical cancer research 10.9 (2004): 3029-3034.
The GST-π gene in located at 11q13 and is coamplified with the cyclin D1 gene (in the same amplicon) in some human solid tumors (breast carcinoma, squamous cell lung carcinoma, bladder carcinomas, and esophageal carcinoma; Ref. 19). The unusual resistance to chemotherapy in MCL compared with other lymphoma entities GST-π overexpression has been associated with resistance to alkylating agents and anthracyclines.  A high GST-π expression (>50% cells stained) was observed in the 24 cases of MCL
MCL is one of the most chemotherapy-drug-resistant lymphomas.
The 10 patients who received sequential CHOP and cytarabine-based chemotherapy at diagnosis did not reach complete remission after CHOP alone but entered into complete remission after high-dose cytarabine (38) . The modest role of the glutathione system in cytarabine resistance compared with alkylating and anthracyclin resistance could be an explanation for the high complete remission rate observed after high-dose cytarabine therapy in MCL (7 , 39)
101) Zhou, Jianbiao, and Wee-Joo Chng. “Identification and targeting leukemia stem cells:The path to the cure for acute myeloid leukemia.” World J Stem Cells 6.4 (2014): 473-484.  Identification and targeting leukemia stem cellsThe path to the cure for acute myeloid leukemia Zhou 2014
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102) FOLIA HISTOCHEMICA ET CYTOBIOLOGICA Vol. 46, No. 2, 2008
pp. 129-135.  Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells  Beata Paj¹k1, Arkadiusz Orzechowski1,2, Barbara Gajkowska1
1Department of Cell Ultrastructure, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland 2Department  Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells Beata Pajak 2008
Saadane et al. [32] found that the inhibition of IKKβ resulted in stabilization of cytoplasmic IKKα, which in turn leads to inhibition of NF-κB translocation. In contrast, Hehner et al. [28] speculated that PN interferes with IKC component that is necessary for the sequential transmission of signals leading to the activation of both IKKs. Since the IKC is non-functional in the absence of NK- κB essential modulator/IKKγ, this latter protein was the potential candidate for the inhibitory activity of parthenolide. Moreover, in all cases, the PN administration blocked DNA-binding of NF-κB. Consequently, lack of NF-κB activity render cancer cells prone to undergo apoptosis or became sensitized to cytokine- and anti-cancer drug-induced cell death [33-36].
PATENT
103)  Use of parthenolide derivatives as antileukemic and cytotoxic agents
US 20150259356 A1
Publication number US20150259356 A1
Publication type Application
Application number US 14/727,126
Publication date Sep 17, 2015
Filing date Jun 1, 2015
Priority date Jul 11, 2003
Also published as US7678904, 9 More »
Inventors Peter A. Crooks, Craig T. Jordan, Xiaochen Wei
Original Assignee University Of Kentucky
104) Zhou, Jianbiao, Ying Qing Ching, and Wee-Joo Chng. “Aberrant nuclear factor-kappa B activity in acute myeloid Leukemia: from molecular pathogenesis to therapeutic target.” Oncotarget 6.8 (2015): 5490.
105) Planta Med. 2003 Nov;69(11):1009-12.
Transport of parthenolide across human intestinal cells (Caco-2).
Khan SI1, Abourashed EA, Khan IA, Walker LA.
This study examined the intestinal epithelial membrane transport of the sesquiterpene lactone parthenolide, a bioactive compound present in the migraine prophylactic herb feverfew. The Caco-2 human colonic cell line was used as an in vitro model of the human intestinal mucosal barrier. The bidirectional transport (apical to basolateral and basolateral to apical) of parthenolide was investigated using Caco-2 monolayers grown on Transwell inserts.
Quantitation of parthenolide was performed using high performance liquid chromatography (HPLC). Apical to basolateral and basolateral to apical permeability coefficients and percent transport were calculated and a potential bioavailability of parthenolide was determined. Sodium fluorescein was used as a marker for paracellular leakage. Parthenolide, at a concentration of 250 microM, demonstrated substantial linear transport across the monolayer. The transport parameters were not affected by the presence of MK-571, an inhibitor of multidrug resistance transporter P-glycoprotein (MRP). Upon comparison of the transport parameters of parthenolide with atenolol under identical conditions and the reported values for model compounds like mannitol and propranolol, it is concluded that parthenolide is effectively absorbed through the intestinal mucosa via a passive diffusion mechanism.
FeverFew Inhibits Platelets
106) Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115(4):447-9.
Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups.  Heptinstall S1, Groenewegen WA, Spangenberg P, Lösche W.
Extracts of feverfew inhibit platelet aggregation and the platelet release reaction. The active components are  believed to be sesquiterpene lactones such as parthenolide. Evidence is presented that inhibition of platelet behaviour is via neutralization of sulphydryl groups either inside or outside the cell. The precise nature of the sulphydryl groups that are susceptible to feverfew and are involved in platelet aggregation and the release reaction have not yet been defined.
107)
DNC NEWS: Feverfew, Stem cells and the treatment of Cancer
June 29, 2005 Subject: Research on the common herb feverfew suggests it may play an important role in the treatment of Cancer.
PATENT
108) Stabilized feverfew formulations
WO 2005082393 A1
patent 4% feverfew
http://www.google.com/patents/WO2005082393A1?cl=en
A Feverfew extract containing 4% parthenolide is available from Galilee Herbal Remedies and as OptiPure Brand (Chemco
Industries, Inc.) as “PharmaFew”. [009] The present invention more advantageously provides a “stabilized”
Feverfew extract having at least about 4% parthenolide by weight of the total weight of the extract. Roy Bouskila, Soft Gel Technologies Inc, Ronald G Udell
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Sulforaphane
109) Sestili, Piero, and Carmela Fimognari. “Cytotoxic and Antitumor Activity of Sulforaphane: The Role of Reactive Oxygen Species.” BioMed Research International 2015 (2015).
SFR is passively absorbed by cells, where it is rapidly conjugated with glutathione (GSH) by glutathione S-transferases (GSTs).
However, after dietary consumption, SFR levels in humans are lower and closer to 3 μM
SFR administered orally protects against animal carcinogenesis and induces antiproliferative effects in human tumor cells in xenograft models.
A second important antitumor mechanism is the ability of SFR to block cell proliferation and induce apoptosis of cancer cells, thus reducing tumor growth.
depletes glutathione
it is important noting that cells treated with high doses of SFR undergo a situation of increased ROS sensitivity since a peculiar capacity of the isothiocyanate consists in depleting the GSH cellular pool [58, 59] (Figure 1), an effect which is particularly severe with high, supranutritional SFR concentrations. Indeed, depletion of GSH deprives cells of a first line, soluble antioxidant defense [53, 60, 61], giving rise to a “vicious oxidative cycle” (ROS production in cells which at the same time are being depleted in GSH) which is indirectly demonstrated by the fact that N-acetylcysteine (NAC) supplementation enhanced cell survival opposing to GSH depletion [57, 58] rather than acting itself as a mere, direct antioxidant.
loss of mitochondrial transmembrane potential, release of cytochrome C, and mitochondrial damage are in effect induced by SFR
A selective toxicity of SFR to cancer cells has been demonstrated in different experimental models.
Leukemia Lymphoma
110)  Fimognari C., Turrini E., Sestili P., et al. Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions. PLoS ONE. 2014;9(7)
Sulforaphane caused a dose-dependent induction of apoptosis in blasts from patients diagnosed with acute lymphoblastic or myeloid leukemia.
We found that synthesized SR caused a dose-dependent induction of apoptosis in acute leukemia cell lines and primary lymphoblasts from patients diagnosed with B-ALL, T-ALL, and AML.
SR controlled the expansion of leukemic cells
As to the concentrations of SR used in this study, they could be not achievable from food supply. However, after a single oral dose of SR at 150 µmol/kg in rat, plasma concentrations of SR equivalents increase to 15.2 µM [46].
111)  Shang, Hung‐Sheng, et al. “Sulforaphane‐induced apoptosis in human leukemia HL‐60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray.” Environmental toxicology (2016).
Breast Cancer
112)  Li, Yanyan, et al. “Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.” Clinical Cancer Research 16.9 (2010): 2580-2590.
A NOD/SCID xenograft model was employed to determine whether sulforaphane could target breast CSCs in vivo,
Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after re-implantation of primary tumor cells into the secondary mice
These findings support the use of sulforaphane for chemoprevention of breast cancer stem cells and warrant further clinical evaluation.
Breast Cencer CAncer stem cells in vitro and in vivo xenograft mouse model
113)  Kallifatidis G, Rausch V, Baumann B, et al. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut. 2009;58:949–63. [PubMed]
An interesting observation is that sulforaphane was able to inhibit stem/progenitor cells at the concentrations (0.5~ 5 μM) that hardly affected the bulk population of cancer cells, implying that sulforaphane is likely to preferentially target stem/progenitor cells compared to the differentiated cancer cells.
These results suggest that sulforaphane was able to eliminate breast CSCs in primary xenografts, thereby abrogating the re-growth of tumors in secondary mice. Taken together with the in vivo Aldefluor assay results, these findings suggest that sulforaphane targets breast CSCs with high potency.
sulforaphane decreased the protein level of β-catenin by up to 85% in MCF7 and SUM159 cells; and the expression of cyclin D1, one of the Wnt/β-catenin target genes, declined by up to 77% as well
As a chemoprevention agent, sulforaphane possesses many advantages, such as high bioavailability and low toxicity
A recent pilot study detected an accumulation of sulforaphane in human breast tissue, with 1.45 ± 1.12 pmol/mg for the right breast and 2.00 ± 1.95 pmol/mg for the left, in eight women who consumed broccoli sprout preparation containing 200 μmol sulforaphane about 1 hr before the surgery (36). These concentrations of sulforaphane are expected to be effective against breast CSCs, based on our in vitro results
114)  Li, Y., and T. Zhang. “Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts.” Future oncology (London, England) 9.8 (2013): 1097-1103.
115)  Wu, S., et al. “Sulforaphane produces antidepressant-and anxiolytic-like effects in adult mice.” Behavioural brain research 301 (2015): 55.
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Sulfasalazine – Mantle Cell Lymphoma
116) Bebb, G., et al. “Sulfasalazine, inhibits growth of mantle cell lymphoma (MCL) cell cultures via cyst (e) ine starvation and delays tumour growth in a newly developed murine MCL model.” BLOOD. Vol. 102. No. 11. 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA: AMER SOC HEMATOLOGY, 2003.
Introduction: Cyst(e)ine deficiency within lymphoid cells leads to a rapid decline in their levels of glutathione (a major free radical scavenger), loss of defense against oxidative stress, and subsequently apoptosis. Lymphoid cells cannot synthesize the amino acid and depend for growth and viability on its uptake from their micro-environment. Since lymphomas have been shown to retain the inability to synthesize cyst(e)ine they are potentially susceptible to cyst(e)ine starvation-based therapy. We have previously demonstrated that sulfasalazine (SASP), a drug used for treatment of severe inflammatory bowel disease and rheumatoid arthritis, is a potent inhibitor of the cystine/glutamate antiporter, xc-, a major plasma membrane cystine transporter. SASP abrogated growth of T and B lymphoma cell cultures via cystine starvation; SASP, administered intraperitoneally, markedly inhibited growth of rat Nb2-U17 lymphoma transplants in Nb rats without major toxicity to the hosts (Anti-Cancer Drugs 14:21, 2003). In the present study we investigated the usefulness of SASP in our newly developed model of MCL, a B-cell non-Hodgkin lymphoma (NHL), characterized by cyclin D1 and BCL2 over-expression. Results: Growth of human MCL cultures in Fischer’s medium, supplemented with 10% fetal bovine serum and antibiotics, was markedly inhibited by SASP at therapeutic concentrations, showing IC50s of 0.13 and 0.30 for Z138C and Granta MCL cultures, respectively. Culture growth arrest could be largely prevented by enhancing cellular cystine uptake using 66 uM 2-mercaptoethanol (reported to promote cystine uptake via the leucine transporter), indicating that the SASP-induced inhibition resulted from cyst(e)ine starvation. A study into the efficacy of SASP in vivo was initiated using SCID/Rag2-M mice injected subcutaneously with Z138C cells (5 million cells/mouse); such a procedure leads to consistent development of tumours within 28 days. When tumours had reached a weight of about 0.1 gr, groups of six mice were treated for 10 consecutive days with saline (controls) or SASP (250 mg/kg body weight i.p., b.i.d.), a dosage well below the maximally tolerated dosage (300 mg/kg every 8 hr). It was found that treatment with SASP inhibited tumour growth, showing a delay in growth of at least 7 days, without major toxicity. Conclusions: SASP has a marked inhibitory effect on growth of MCL cell lines in vitro, an effect also seen in vivo in our murine SC MCL model. SASP may represent a novel approach for MCL treatment. The precise molecular consequences of SASP treatment on MCL cells warrant further investigation. Additional studies on the effect of SASP at higher dosages and in combination with cyclophosphamide and targeted therapies, eg. ASO and monoclonal antibodies against bcl-2, are in progress.
Lymphoma
117)   Gout, Peter W., Chris R. Simms, and May C. Robertson. “In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine.” Anti-cancer drugs 14.1 (2003): 21-29.
Sulfasalazine (SASP) is a novel, potent inhibitor of cellular cystine uptake mediated by the x(c)- cystine/glutamate antiporter. Lymphoid cells cannot synthesize cyst(e)ine and depend for growth on its uptake from their micro-environment. We previously showed that SASP (0.2 mM) can abrogate lymphoma cell proliferation in vitro by specifically inhibiting x(c)- -mediated cystine uptake. Intraperitoneal administration of SASP to Noble rats markedly suppressed Nb2-U17 rat lymphoma transplant growth, notably without major toxicity to the hosts. Since Nb2-U17 cells are x(c)- -deficient, the growth arrest was apparently not due to SASP-tumor cell interaction, but possibly to interference with x(c)- -mediated cysteine secretion by somatic cells. In this study we found that replication of x(c)- -deficient Nb2-11 lymphoma cells can be sustained in vitro, in the absence of cystine uptake enhancers, by co-culturing with IMR-90 fibroblasts known to secrete cysteine. SASP, at 0.15 and 0.2 mM, arrested replication of fibroblast-driven Nb2-11 cells by 93 and 100%, respectively, without impeding fibroblast proliferation. Addition of 2-mercapto-ethanol (60 microM), a cystine uptake enhancer, almost completely prevented this growth arrest, indicating that SASP specifically inhibited cysteine secretion by the fibroblasts, a process based on x(c)- -mediated cystine uptake. It is proposed that the lymphoma growth-inhibitory activity of SASP in vivo involves inhibition of cysteine secretion by tumor-associated somatic cells (macrophages, dendritic cells), leading to cysteine starvation of the tumor cells and apoptosis. The difference between the lymphoma cells and fibroblasts in sensitivity to SASP treatment is consistent with the marked antitumor effect of SASP lacking significant side effects.
Small cell Lung cancer full pdf
118) Guan, Jun, et al. “The x c− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine.” Cancer chemotherapy and pharmacology 64.3 (2009): 463-472.
Conclusions The xc- cystine/glutamate antiporter is
potentially useful as a target for therapy of SCLC based on
glutathione depletion. Sulfasalazine may be readily used
for this approach, especially in combination chemotherapy.
pancreatic full pdf
119) Lo, M., et al. “Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer.” Current Oncology 17.3 (2010): 9-16.
Breast
120) Narang, Vishal S., et al. “Suppression of cystine uptake by sulfasalazine inhibits proliferation of human mammary carcinoma cells.” Anticancer research 23.6C (2002): 4571-4579.
Prostate
121) Doxsee, Daniel W., et al. “Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy.” The Prostate 67.2 (2007): 162-171.
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Butyrate
2016
122) Zhang, J., et al. “Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis.” PloS one 11.1 (2016): e0147218.
2007
123) Pajak, B., A. Orzechowski, and B. Gajkowska. “Molecular basis of sodium butyrate-dependent proapoptotic activity in cancer cells.” Advances in Medical Sciences (De Gruyter Open) 52 (2007).
This review outlines the molecular events that accompany the antitumor action of sodium butyrate (NaBt). Butyrate, alow-molecular weight four-carbon chain volatile fatty acid (VFA) has been previously shown to withdraw cells from cell cycle or to promote cell differentiation, and finally to induce programmed cell death. Recent advances in molecular biology indicate, that this product of large bowel microbial fermentation of dietary fiber, might evoke the above-mentioned effects by indirect action on genes. NaBt was shown to inhibit histone deacetylase activity, allowing DNA binding of several transcription factors. Higher genomic activity leads to the higher expression of proapoptotic genes, higher level of their protein products and elevated sensitivity to death ligand-induced apoptosis. Cancer cells might be arrested in G1 phase of cell cycle in a p21-dependent manner. Proapoptotic activity of NaBt includes higher expression of membrane death receptors (DR4/5), higher level and activation of Smad3 protein in TGF-beta-dependent apoptotic pathway, lower level of antiapoptotic proteins (cFLIP, XIAP) and activation of proapoptotic tBid protein. Thus, both intrinsic and extrinsic apoptotic pathways are stimulated to ampify the apoptotic signals. These effects are specific for tumor but not for regular cells. Unique properties of NaBt make this agent a promising metabolic inhibitor to retard tumorigenesis to suppress tumor growth.
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Inhibits Telormerase Activity
124) Choi, Yung Hyun. “Apoptosis of U937 human leukemic cells by sodium butyrate is associated with inhibition of telomerase activity.” International journal of oncology 29.5 (2006): 1207-1213.
Sodium butyrate as a histone deacetylase inhibitor.  Exposure of U937 cells to sodium butyrate resulted in growth inhibition and induction of apoptosis in a dose-dependent manner.
The increase in apoptosis was associated with the up-regulation in pro-apoptotic Bax expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL.
sodium butyrate markedly inhibited the activity of telomerase and the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively downregulated by sodium butyrate.
In addition to the deregulation of apoptosis, it is increasingly clear that the process of neoplasia is characterized by the activation of telomerase that adds telomeric repeats to the ends of replicating chromosomes, telomeres
Critically short telomeres are suggested to cause irreversible cell growth arrest and cellular senescence.
telomerase reactivation is a rate-limiting step in cellular immortality and carcinogenesis, and telomerase repression can act as a tumor-suppressive mechanism.
Sodium butyrate is a short chain fatty acid normally produced as a result of bacterial fermentation of fiber in mammalian intestines, representing one of the end products of carbohydrate breakdown
the ratio between the level of proapoptotic Bax and that of the anti-apoptotic factor Bcl-2 determines whether a cell responds to an apoptotic signal.
there was a concentration-dependent down-regulation of Bcl-2 members such as Bcl-2 and Bcl-XL in sodium butyrate-treated U937 cells, but the levels of Bax were up-regulated, resulting in an increase in the ratio of
Bax/Bcl-2 and/or Bcl-XL.
In conclusion, our results indicated that sodium butyrate potently suppresses the proliferation of U937 human leukemic cells by inducting apoptosis through an increase of Bax expression and activation of caspase-3. The growth inhibitory effects of sodium butyrate were also associated with a specific inhibition of hTERT expression and telomerase activity.
Lauric Acid – coconut oil
2013 full pdf
125) Fauser, J. K., et al. “Induction of apoptosis by the medium-chain length fatty acid lauric acid in colon cancer cells due to induction of oxidative stress.” Chemotherapy 59.3 (2013): 214-224.
Lauric acid, as a component of triglycerides, comprises about half of the fatty acid content in coconut milk,  coconut oil, laurel oil, and palm kernel oil. Compared to butyrate, lauric acid displayed preferential antineoplastic properties, including induction of apoptosis in a CRC cell line.
The SCFA butyrate has demonstrated the capacity to induce apoptosis by: inhibiting histone deacetylase activity, inducing cell cycle arrest, promoting differentiation, activating NF-κB, downregulating α 2 β 1 , modifying glucose availability, and inducing caspase activation in CRC cell lines [1, 2, 9–12] .
126) Jurečeková, Jana, et al. “Targeting of Bcl-2 family proteins for treatment of acute leukaemia.” General physiology and biophysics 30 (2011): S3-S12.
127) Fauser, Jane Kathryn. Medium Chain Fatty Acids and Wnt/β-Catenin Inhibitors as Adjunctive Colorectal Cancer Chemotherapeutic Agents. Diss. The University of Adelaide, 2012.
128) Nohara, Kazunari, Yoshiko Yokoyama, and Kazutaka Kano. “The Important Role of Caspase-10 in Sodium Butyrate.” Kobe J. Med. Sci 53.5 (2007): 265-273.
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Ivermectin
2015
129 )  Draganov, Dobrin, et al. “Modulation of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).
We found that Ivermectin kills mouse and human triple-negative breast cancer (TNBC) cells through augmented P2X7-dependent purinergic signaling associated with caspase-1 and caspase-3 activation.
FIg 7 Model of P2X4/P2X7/Pannexin-1-induced cancer cell death.
Ivermectin induces P2X4/P2X7-dependent activation of Pannexin-1 channels and release of ATP. The release of ATP might be transiently protective, but only in cell types that are highly sensitive to Ivermectin-induces cell swelling when ATP and Ca2+ signaling are essential for control of cell volume. In cancer cells where no cell size changes can be observed (for example human TNBC MDA-MB-231 cells), high concentrations of ATP (1–3 mM) immediately enhance Ivermectin cytotoxicity. Potentiated P2X7 receptor signaling drives a fast progressing necrotic/pyroptotic mechanism driven by NADPH oxidases-generated ROS, cytosolic Ca2+/CaMKII activation, and MPTP, and characterized by caspase-1 cleavage, due to possible NLRP3 inflammasome activation. Necrotic killing is followed by a slower progressing apoptotic cell death program mediated by caspase-3 activation. The failure of the default apoptotic pathway might be attributed to faster activation of caspase-1, inadequate autophagic control of mitochondrial MPTP, collapse of cellular energy metabolism, resulting in rapid progression of necrotic cell death. Damage to mitochondria and ER stress as well as potential depletion of cellular ATP reserves simultaneously promote autophagy that might render even the slower apoptotic pathway immunogenic.
2014  full free
130)  Melotti, Alice, et al. “The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.
as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.
We find that macrocyclic lactones of the Avermectin family have specific anti-WNT-TCF response activity in human cancer cells and that the clinically approved compound Ivermectin (EMEA- and FDA-approved) is a specific WNT-TCF response blocker at low micromolar concentrations.
cancer stem cells
Pre-treatment with Ivermectin and Selamectin inhibits colon cancer stem cell self-renewal in clonogenic spheroid assays
These results suggest an action on both the bulk of the tumor and its cancer stem cells.
Moreover, they might also be useful as routine prophylactic agents, for instance against nascent TCF-dependent intestinal tumors in patients with familial polyposis and against nascent sporadic colon tumors in the general aging population.
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131) O’neill, Paul M., Victoria E. Barton, and Stephen A. Ward. “The molecular mechanism of action of artemisinin—the debate continues.” Molecules 15.3 (2010): 1705-1721. Molecular Mechanism of Action of Artemisinine Debate ONeill 2010
132) Robert, Anne, Jérôme Cazelles, and Bernard Meunier. “Characterization of the alkylation product of heme by the antimalarial drug artemisinin.” Angewandte Chemie International Edition 40.10 (2001): 1954-1957.
133)  full free pdf
Mathur, Rohit, et al. “Targeting Wnt pathway in mantle cell lymphoma-initiating cells.” Journal of hematology & oncology 8.1 (2015): 63. Targeting Wnt pathway in mantle cell lymphoma initiating cells Mathur 2015
134)  Li, Yanyan, et al. “Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.” The Journal of nutritional biochemistry 22.9 (2011): 799-806.
135)  Rodova, Mariana, et al. “Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.” PloS one 7.9 (2012): e46083.
Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
HDAC Inhibitors in Mantel Cell
136) Heider, Ulrike, et al. “Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma.” European journal of haematology 76.1 (2006): 42-50.
Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid vorinostat (SAHA) for 8-72 h.
Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells.
METHODS:  Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed.
RESULTS:  The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB.
CONCLUSION:  Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach.
137) Ivermectin pharmacology and therapeutic applications Sunita Chhaiya 2012  Chhaiya, Sunita B., et al. “IJBCP International Journal of Basic & Clinical Pharmacology.” International Journal 2.6 (2013): 799. Ivermectin pharmacology and therapeutic applications Sunita Chhaiya 2012
Pediculosis head lice dosage- Two 200 mcg/kg tablets a week apart. (12 mg tablet for a 60 kg male).
138) NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011  NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011
Berberine  – Berberine inhibits WNT Pathways
139)  Biofactors. 2013 Nov-Dec;39(6):652-62. Berberine acts as a natural inhibitor of Wnt/β-catenin signaling–identification of more active 13-arylalkyl derivatives. Albring KF1, Weidemüller J, Mittag S, Weiske J, Friedrich K, Geroni MC, Lombardi P, Huber O.
Aberrant activation of the canonical Wnt/β-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in β-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/β-catenin signaling is of specific therapeutic interest.  As a result of berberine treatment, cellular levels of active β-catenin were reduced concomitant with an increase in the expression of E-cadherin.
140)  Eur J Pharmacol. 2014 Oct 5;740:584-95. Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer.Jabbarzadeh Kaboli P1, Rahmat A2, Ismail P3, Ling KH4.
Berberine was shown to be effective in inhibiting cell proliferation and promoting apoptosis invarious cancerous cells. Some signaling pathways affected by berberine, including the MAP (mitogen-activated protein) kinase and Wnt/β-catenin pathways, are critical for reducing cellular migration and sensitivity to various growth factors.
Epiphany Against cancer
full free pdf
141)  Guamán Ortiz, Luis Miguel, et al. “Berberine, an epiphany against cancer.” Molecules 19.8 (2014):  12349-12367.
BBR treatment promotes cell cycle arrest and death in human cancer cell lines, coupled to an increased expression of apoptotic factors
BBR functions as an inhibitor of the telomere elongation by blocking the telomerase activity through formation of a G-quadruplex with telomeric DNA
BBR has the potential to modulate and regulate Wnt/β-catenin pathway [56], which in normal cells is inactivated by ubiquitination and subsequent degradation of the β-catenin protein,
BBR was proved to alter the mitochondrial membrane potential
(MMP), inhibit mitochondrial respiration leading to mitochondrial dysfunction and regulate the expression of Bcl-2 family members, as Mcl-1 [45,47]. Alterations in mitochondrial membrane stimulate the release of cytochrome c promoting the formation of reactive oxygen species (ROS) that trigger apoptosis that requires the activation of caspases and poly(ADP-ribose) polymerase-1 (PARP-1)
cleavage
Silibinin – Inhibits WNT pathway

full free pdf
142) Tiwari, Prabha, and K. P. Mishra. “Silibinin in cancer therapy: A promising prospect.” Cancer Research Frontiers 1.3 (2015): 303-318.
Silibinin also inhibited Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human breast cancer cells MDA-MB-231 and T-47D
Exogenous SOD markedly enhanced silibinin-induced apoptosis
clinical trials for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Silymarin (The target dose of silibinin was 5.1 mg/kg/day) was administered orally for 28 days and it significantally reduced liver toxicity in children with ALL (74). Recently a new silibinin drug formulation Legasil® administration improved hepatic failure due to extensive liver infiltration in a breast cancer patient (75).
A Phase II Study to Assess Efficacy of Combined Treatment with Erlotinib (Tarceva) and Silybin-phytosome (Siliphos) in Patients with EGFR mutant lung adenocarcinoma is going on (ClinicalTrials.gov Identifier:
Silibinin has also shown promising results against cancer stem cells, supporting further development of anti-cancer therapeutics that target tumor stem cells.
143) Siegel, Abby B., et al. “A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.” Integrative cancer therapies (2013): 1534735413490798.
Targeting Cancer Stem Cells – Pterostilbene
144) Wu, Chi-Hao, et al. “Targeting cancer stem cells in breast cancer: potential anticancer properties of 6-shogaol and pterostilbene.” Journal of agricultural and food chemistry 63.9 (2015): 2432-2441.
Breast cancer stem cells (BCSCs) constitute a small fraction of the primary tumor that can self-renew and become a drug-resistant cell population, thus limiting the treatment effects of chemotherapeutic drugs. The present study evaluated the cytotoxic effects of five phytochemicals including 6-gingerol (6-G), 6-shogaol (6-S), 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-HF), nobiletin (NOL), and pterostilbene (PTE) on MCF-7 breast cancer cells and BCSCs. The results showed that 6-G, 6-S, and PTE selectively killed BCSCs and had high sensitivity for BCSCs isolated from MCF-7 cells that expressed the surface antigen CD44(+)/CD24(-). 6-S and PTE induced cell necrosis phenomena such as membrane injury and bleb formation in BCSCs and inhibited mammosphere formation. In addition, 6-S and PTE increased the sensitivity of isolated BCSCs to chemotherapeutic drugs and significantly increased the anticancer activity of paclitaxel. Analysis of the underlying mechanism showed that 6-S and PTE decreased the expression of the surface antigen CD44 on BCSCs and promoted β-catenin phosphorylation through the inhibition of hedgehog/Akt/GSK3β signaling, thus decreasing the protein expression of downstream c-Myc and cyclin D1 and reducing BCSC stemness.
human lung adenocarcinoma
145)  Yang, Yang, et al. “Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.” PloS one 8.5 (2013): e62652.
antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway
PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells.
reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS).
Activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment.
Down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment.
Chloroquin and Pterostilbene – autophagy inhibitor potentiated pterostilbene effect
146) Papandreou, Ioanna, et al. “Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.” Experimental cell research 339.1 (2015): 147-153.
We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER-stress responsive luciferase gene. After secondary screening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecular analysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia.
CONCLUSIONS:  Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application.
147) vorinostat HDAC Inhibitors
Sakajiri, Sakura, et al. “Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines.” Experimental hematology 33.1 (2005): 53-61.
Methylation of tumor suppressor genes is frequently observed in human cancers. These genes are silenced by histone deacetylase (HDAC) recruited by methylated DNA in their promoter regions. HDAC removes acetyl groups from histones and prevents the basic transcriptional machinary access to the target gene, leading to transcriptional repression. HDAC inhibitors (HDACIs) can restore the expression of the tumor suppressor and/or cell cycle regulatory genes in cancer cells and block the cellular proliferation of these cells. In this study, we investigated the in vitro antiproliferative activities of the HDACIs, suberoylanilide hydroxamic acid (SAHA), and valproic acid against 14 human lymphoid cancer cell lines. All of these cell lines were sensitive to the antiproliferative effects of the HDACI. SAHA induced either G1 or G2-M arrest as well as apoptosis. SAHA downregulated cyclin D1 and D2, and upregulated p53, p21, and p27. Chromatin immunoprecipitation analysis revealed a remarkable increase in the level of acetylated histones associated with the p21 promoter after SAHA treatment. In nude mice, SAHA significantly inhibited growth of a mantle cell lymphoma without major toxic side effects. In summary, HDACIs are promising therapeutic agents for human lymphoid cancers.
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HerbalZym
148) Modulation of β-catenin signaling by natural agents induces apoptotic cell death in many common cancers, including colon cancer, breast cancer and prostate cancer. Part 1
149) PART TWO
Berberine reduces cellular levels of active β-catenin and inhibits β-catenin transcriptional activity. Silymarin, honokiol, lupeol, genistein, gugulipid, resveratrol, quercetin, EGCG, lycopene, sulforaphane, ellagic acid, Vitamin D, and omega-3-polyunsaturated fatty acids also antagonize or modulate Wnt/β-catenin signaling. We believe that these natural agents that are non-toxic in nature could be used either alone or in combination with conventional therapeutics for the prevention and/or treatment of a variety of cancers.
Parthenolide
150) Bioavailable Parthenolide Histone Deacetylase (HDAC) Inhibitor, Part 1
151) Bioavailable Parthenolide Histone Deacetylase (HDAC) Inhibitor, Part 2
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