Targeting Cancer Stem Cells
with NonToxic Therapies
by Jeffrey Dach MD
When Jim was 36 year old, he was diagnosed with acute myeloblastic
leukemia with symptoms of fatigue, anemia, and extremely high white
count on his blood panel. Over three years, Jim received seven
chemotherapy treatments, each one giving him a temporary remission
shorter than the last one. Eventually the chemotherapy was no longer
effective, the cancer cells became resistant to chemotherapy. After
exhausting all of the usual treatments, the doctors offered Jim
allogeneic hematopoetic stem cell transplantation, a procedure which
obliterates the patient’s bone marrow with high dose chemotherapy. The
patient is then “rescued” with donor bone marrow stem cells from a
family member or donor bank. This procedure is associated with
considerable morbidity and mortality from infection and graft vs. host
disease. The high dose chemotherapy produces permanent, irreversible
infertility. Jim had the procedure and is alive and doing well three
years later.
Upper left image poster courtesy of Cancer Stem Cell Meeting 2012 Cambridge Cancer Stem Cell Symposium.
What can we learn from Jim’s story?
The first lesson is that hematologic malignancies, and all other
cancers for that matter, tend to come back (relapse) even after
complete remission induced by cytotoxic chemotherapy. For many years,
the reason for this cancer recurrence was unknown. However, in the past
decade, the reason has been discovered.
Two Populations of Cancer Cells
There are actually two distinct populations of cancer cells in the
cancer victim. The bulky tumor masses are caused by rapidly replicating
cancer cells, highly sensitive to killing effects of chemotherapy.
However, a subset of these cancer cells lurk within the tumor mass,
hiding in a dormant state, not actively replicating. These are the
cancer “stem cells”
which are resistant to conventional cytotoxic chemotherapy, biding
their time, waiting for a future opportunity to reactivate and seed
metastatic cancer throughout the body.
Above image courtesy of Case Western Reserve Cancer Stem Cell Conference.
This explains Jim’s futile experience with chemotherapy which kills
off the rapidly replicating leukemia cells, while leaving the dormant
leukemia “stem cells” unharmed. This is also true for most other solid
organ cancers. The solution, of course, is to address the dormant
cancer “stem cell”, at the same time as the rapidly replicating cancer
cells.(1,1A)
Unfortunately, modern day oncology/ hematology doctors are oblivious
to this important lesson, and continue to mindlessly treat their
patients with the same chemotherapy protocols as before. Even though
this information is in their own oncology/hematology journals, they
cannot bring themselves to acknowledge it.
Sadly, since their doctors will not help them, patients are left to
fend for themselves. In order to get off the chemotherapy
merri-go-round, the patient must learn about non-toxic targeted
therapies which kill cancer stem cells. These are widely available. As
we will see below, some of these therapies are supplements at the
health food store, and some are common drugs requiring a doctor’s
prescription. With knowledge of n
on-toxic targeted therapies, a durable remission after the last chemotherapy treatment can be achieved.
Left Image Ovarian Cancer Stem Cells Courtesy of Yale News.
Many Natural Substance Target Cancer Stem Cells(12)
You might be surprised to know there are 3,000 plant species having
anti-cancer activity.(1B) In fact, there are hundreds of non-toxic
natural substances that target cancer stem cells. (12) There are so
many to choose from, one must be selective, so we will discuss only a
few of them below: (10-19)
Curcumin
The food spice, Curcumin (tumeric) is widely available as a
nutritional supplement in highly absorbance forms such as Meriva(r),
Cogumen (Longvida) or Lipospheric Curcumin.
Dr Huang reports in 2016 that “
Curcumin Induces Apoptosis of Colorectal Cancer Stem Cells by Coupling with CD44 Marker”.
Dr Huang studied colorectal cancer stem cells, and found curcumin couples with the CD44 cancer stem cell membrane marker,
and “might have some blocking effect on the transport of glutamine into the cells, thus decreasing the glutamine content in the CD44+ cells and inducing apoptosis.”(2)
Dr Chung reported in 2015 that both “
Curcumin and EGCG Epigallocatechin Gallate Inhibit the Cancer Stem Cells . (3) Dr Chung reported the cancer stem cell marker was denoted by the
CD44+ protein. The CD44+ cell population decreased following curcumin and EGCG (from Green Tea). (3)
Dr
Hasanali in 2012 reported that Curcumin inhibits Nuclear Factor Kappa
Beta activation and Downregulate Cyclin D1 in Mantle Cell Lymphoma,
thereby inducing apoptosis. (4)
Left image: molecular structure of curcumin courtesy of Wikimedia commons.
Dr Shishodia in 2005 reported that “
Curcumin inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in
mantle cell lymphoma.” (5)
The authors reported:
“the expression of
all NF-kappaB-regulated gene products were downregulated by Curcumin
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.”
Dr Choudhuri reported in 2005 found that “
Curcumin selectively induces apoptosis in cancer cells with deregulated cyclin D1 at G2 phase of cell cycle.”(6) Normal cells were left unharmed. (6)
Drug inventors have been busy with new ideas to make curcumin more
bioavailable and more effective, such as Curcumin nanodiscs. (7-9) A
massive body of basic science and medical studies on Curcumin shows the
natural plant substance kills cancer stem cells while sparing normal
cells as a non-toxic targeted therapy. (2-9)
Dr Peter Sordillo wrote an excellent summary of curcumin’s ability to kill cancer stem cells in ,”
Curcumin and Cancer Stem Cells” AntiCancer Research 2015 (10)
Dr Sordillo reports that Curcumin inhibits release of cancer associated
cytokines, IL6 and IL8, resulting in inhibition and suppression of
cancer stem cells. Both the WNT and Notch pathways are important for
cancer stem cell survival. Curcumin acts to inhibit and block multiple
points along the Wnt pathway and Nctch pathways, downregulating
β-catenin and the genes for VEGF, cyclin D1 and c-Myc. Amazingly,
Curcumin has no deleterious effects on normal stem cells, and targets
only the cancer stem cells.
The reason offered for this selectivity is:
1) Curcumin has much greater uptake by cancer cells compared to normal cells.
2) Curcumin affects the microenvironment around Cancer Stem Cells by
suppressing release of proinflammatory cytokines IL6 and IL8.
3) Curcumin induces Cancer Stem Cells to undergo cell differentiation
into a mature cells which then undergo spontaneous or drug induced
apoptosis.
4) Curcumin
suppresses the Wnt pathway in Cancer Stem Cells with
inhibition of β-catenin, yet has the opposite effect on neural stem cells as it stimulates neurogenesis. (10)
Curcumin is highly lipophilic, and crosses the blood–brain barrier
easily, and therefore suggested by Dr Sordillo as a “sensitizer” along
with conventional chemotherapy for treatment of Glioblastoma.(11B)
Curcumin and Chemo Resistant AML Stem Cells
Dr Jia Rao studied the anti-cancer effects of Curcumin in 9 separate
acute myelogenous leukemia cell lines. (11C) Dr Rao reports in 2011
that chemotherapy resistance in acute myelogenous leukemia may be due to
upregulation of the anti-apoptotic protein Bcl-2 in CD34+ cancer stem
cells. Dr Rao found that treatment of the cancer stem cells with
Curcumin reduces the Bcl-2 protein levels, leading to apoptosis
(programmed cell death) while showing no ill effects on normal cells.
“Curcumin demonstrated no major toxicities in phase I and II clinical
studies at doses of up to 8 g/day”.(11C)
Berberine Synergy with Curcu
min
Berberine, also a WNT pathway inhibitor, was found synergistic when combined with Curcumin. (11A)
Berberine
Also called the Berberine (Oregon Grape) Berberine is a natural WNT
pathway inhibitor (48-51) Berberine is actually patented as a targeted
cancer stem cell therapy.(51)
See: Hsieh, Hsiu-Mei, et al. “
Berberine for inhibiting cancer stem cell” U.S. Patent Application No. 14/790,154.
Berberine
is a commonly used herbal extract with many health benefits.
Anti-cancer activity of Berberine is through inhibition of the
WNT/B-Catenin pathway (48-50). Berberine alters mitochondrial membrane
potential, promotes release of cytochrome C, and triggers apoptosis in
the cancer cell.(50)
Left image: chemical structure of Berberine courtesy of wikimedia commons.
In 2013, Dr Liu
studied anticancer effects
of Berberine in a leukemia cell line lacking p53 finding Berberine
induced apoptotic cell death via suppression of the anti-apoptotic
protein (XIAP) which then inhibited MDM2 expression. This also
increased the sensitivity of leukemia cells to doxorubicin-induced
apoptosis.(48A)
Milk Thistle
Milk Thistle (Silybin-phytosome –
Siliphos) is a
widely used herbal extract which inhibits the WNT/B-Catenin pathway.
(52-54) A number of clinical trials have shown benefits and promising
effects against cancer stem cells. (52-54)
Sulforaphane
Sulforaphane, a Brocolli Extract, down regulates glutathione. and Inhibits WNT signaling (13-19)
Dr Kallifatidis et al studied
Sulforaphane in
a 2009 study of pancreatic cancer cells.(14) The authors report
sulforaphane “targets pancreatic tumour-initiating cells by
NF-kappaB-induced antiapoptotic signalling” The authors state:
“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.”(14) “As
a chemoprevention agent, sulforaphane possesses many advantages, such
as high bioavailability and low toxicity.”
In a p53 depleted colon cancer cell model, Dr Rudolph from the Czech Republic in 2011 found that sulforaphane induced
lysosome and mitochondria-dependent cell death in colon cancer cells with deleted p53. The effects were independent of P53 status.
Sulforaphane
is a small molecule which easily crosses blood brain barrier producing
anti-depressant and anti-anxiety effects in animal studies.
(16) Sulforaphane is neuroprotective and
improves cognitive function after traumatic brain injury. The combination of Resveratrol(Pterostilbene) and Sulforaphane was
effective against human glioblastoma in vitro cell cultures.
Sulforaphane is a HDAC (histone deacetylase inhibitor) and
suppresses human prostate cancer in animal xenograft model. Sulforaphane Anti-Cancer effects are
independent of mutated P53 status.
Pterostilbene Synergy With Chloroquin
Pterostilbene is a natural analog of Resveratrol found in blueberries,
which is more bioavailable and more potent than resveratrol in activity
against many different cancer cell types. (54-55)
Dr Chi-Hao Wu
reported in
2015 that pterostilbene targets breast cancer stem cells.(54) Using
breast cancer cells (MCF-7) in vitro, his study showed
that Pterotilbene selectively killed Breast Cancer Stem Cells which
express the CD44 surface antigen.
In addition,
Pterostilbene increased the sensitivity of Breast Cancer Stem Cells to
killing effects of chemotherapy. The underlying mechanism of
Pterostilbene was degradation of β-catenin, thus inhibiting expression
of cancer growth factors C-Myc and Cyclin D1.(54)
Dr Yang reported in 2013 that “
Pterostilbene exerts antitumor activity” in
adenocarcinoma of the lung, both in vitro and in vivo with mouse tumor
xenografts. (55) Dr Yang showed pterostilbene significantly decreased
the Mitochondrial Membrane Potential and increased Reactive Oxygen
Species (ROS) with depletion of intracellular glutathione i the cancer
cells. Expression of apoptosis pathway proteins BAX and Cytochrome C
were upregulated.(55)
Dr Papandreou reported in 2015 on their study in which 1,726 small
molecules were screened for activation of the Endoplamic Reticulum (ER)
stress response Gene. They said “
plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group.“
(56)
Dr Papandreou then determined by molecular analysis that Pterostilbene
blocks Wnt/B-Catenin pathway and also induces autophagy in acute
lymphoblastic leukemia cells. The authors found that:
“combining pterostilbene (to induce
ER stress) with chloroquine (to inhibit autophagy) leads to significant
cellular toxicity in cells from aggressive acute lymphoblastic leukemia.“(56)
Parthenolide – Feverfew (41-43)
Parthenolide is the major active component in Feverfew, an herbal
medicine used for centuries for migraine headache, and more recently for
rheumatoid arthritis.
Left image : Feverew courtesy of wikimedia commons.
Dr Monica Guzman
reported in 2005 Blood , that Parthenolide is a potent inhibitor of NFKB (Nuclear Factor Kappa Beta) and:
“induces robust
apoptosis in primary human acute melogenous leukemia (AML) cells while
sparing normal hematopoietic cells. Furthermore, partheolide (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).” (41)
Dr Shanshan Pei reported in 2013 that Parthenolide targets the
aberrant, upregulated glutathione metabolism in leukemia cancer stem
cells by inducing almost complete glutatione depletion and severe cell
death.(42) At the same time, there was only limited and transient
perturbation in normal hematopoetic cells.
Dr Shanshan Pei noticed that Parthenolide contains an active α,β-unsaturated-γ-lactone group (
see left image: From Fig. 3B, red ellipse denotes active area) that readily reacts with free thiol group of glutathione.(42)
In addition, the authors tested the combined effects of Pathenolide
with commonly used chemotherapy drugs Ara-C and Idarubicin, finding
augmented synergistic effects with anti-cancer activity substantially
increased.
Repurposed Drugs Effective Against Cancer Stem Cells:
Sulfasalazine (Azulfidine)
Sulfasalazine (Azulfidine) is an old rheumatology drug which targets
cancer stem cells by inhibiting the xCT signal pathway for cystine
uptake. By starving the cancer stem cell of cystine, intracellular
glutathione is depleted, rendering the cancer cell defenseless to
oxidative stress, ultimately resulting in cell death from oxidative
damage.
Dr Shitara’s group reported at the 2014 ASCO Annual Meeting on the “
effect of sulfasalazine (SSZ) on cancer stem-like cells (CSCs) via inhibiting the xCT signal pathway” . Dr Shitera reported that the
CD44 surface adhesion molecule is expressed in
cancer stem-like cells. They found cancer stem cells have a variant (
CD44v) which interacts
with xCT, the glutamate-cystine transporter and maintains high levels of the
intracellular reduced glutathione (GSH). They found that “
Sulfasalazine
acts as an xCT inhibitor which suppressed CD44v-dependent tumor growth
and increased sensitivity to cytotoxic drugs in vivo study.”(20)
Dr Ishimoto in a 2011 study also found Sulfasalazine inhibited the
xCTmembrane transporter of cystine uptake, thereby suppresses
CD44-Dependent Tumor Growth in cancer stem cells in vivo.(21) Dr
Ishimoto states, ”
The activity of xCT-mediated cystine uptake in
cancer cells is highly associated with cell proliferation,
chemoresistance, and tumor growth.“(21)
Many studies show sulfasalazine effective for other cancers as well,
including head and neck cancer, breast, prostate, lung, pancreatic
cancer and lymphoma (20-38) . Sulfasalazine was effective against
Mantle Cell lymphoma cells in vitro.(23) Although considered safe as a
long term drug treatment in rheumatology patients, sulfasalazine crosses
the blood brain barrier and can result in CNS toxicity, so caution is
advised. (29-30) Sufasalazine is
poorly absorbed,
(3-12%) with a 5-10 hour half life. Sulfasalazine is cleaved by
colonic bacteria into sulfapyridine and 5-ASA, thought to be active in
treatment of inflammatory bowel disease. (
Klotz 1985)
Mefloquin was second most active after Ivermectin
Chloroquin and Mefloquin (Lariam) are old Anti-Malaria drugs – They inhibit autophagy and serve as Lysosomal disruptors.
Dr Sukhai screened a library of drugs for greatest activity against
AML (Acute myelogenous Leukemia stem cells. Dr Sukhai found Mefloquin
was second most active after Ivermectin with an EC50 of less than 8
microM.(39) Mefloquin was less toxic to normal cells. (39) Mefloquine
specifically targets lysosomal function and accumulates in lysosomes of
the malarial parasite. Dr. Sukhai found that Mefloquine directly
disrupted lysosomes of Acute Myelogenous Leukemia cells (and progenitor
stem cells) in a dose-dependent manner, as measured by release of
cathepsins into the cytosol.
(39) Normal hematopoietic cells were unharmed. (39)
Serum concentrations of mefloquine up to 5 μM have been reported in
individuals receiving 250 mg weekly for malaria prophylaxis . Thus,
antileukemia concentrations of mefloquine may be pharmacologically
achievable.(39)
Combination of Artemisinin with Mefloquin synergistic
The most synergistic combinations from Dr Sukhai’s screening efforts
was Mefloquin with the anti-malarial drug, artemisinin. The two in
combination synergistically increased ROS (reactive oxygen sspecies)
production.(39)
“Mefloquine potently inhibits proliferation and induces apoptosis of a panel of human gastric cancer cell lines, with EC50 ~
0.5-0.7 µM.
In two independent gastric cancer xenograft mouse models, mefloquine significantly inhibits growth of both tumors”.(59) Mefloquin was effective agains prostate cancer cell lines(63)
The mechanism of mefloquin (64) :Mefloquine caused an expansion of the lysosomal apparatus, earliest seen by 24 h and lasting for some 7 days.
(1) mefloquine is a lysosomotropic drug that accumulates in lysosomes;
(2) mefloquine impairs lipid degradation with ensuing accumulation of lipids in lysosomes; and
(3) lysosomal trapping explains the high volume distribution of mefloquine.(64)
Dr Sachlos screened
590 well-established annotated compounds
from the NIH Clinical Collection and Canadian Compound Collection,
finding that Mefloquin induced differentiation of neoplastic
hematopoetic PSCs (human stem cells) while not affecting normal
hPSCs.(human stem cells). (69) Within the top ten candidates,
mefloquine were found to possess EC50 values
lower than the 10 µM target threshold, with no effect on normal hematopoiesis. Mefloquin as a cancer treatment was patented by the University of California in 2002. (70)
Mefloquine Neuro-Toxicity
Caution is advised before using Mefloquine as well as other
Quinolones. Although originally marketed as safe for malaria
prophylaxis, recent
studies show an alarming incidence of neurologic toxicity, which may be “clinically occult , and in some cases, irreversible.
(Remington Nevin 2014).
A possible mechanism of Mefloquin toxicity was elucidated by Dr Anthony Mawson, in his 2013
article, “Mefloquine use, psychosis, and violence: a retinoid toxicity hypothesis,” Dr Mawson says:
“The use of mefloquine in the prevention and treatment of malaria
has been increasingly linked to a broad range of neuropsychiatric
effects, including depression, psychosis, and violence. The symptoms of
mefloquine toxicity may result from the spillage of stored retinoids
from the damaged liver into the circulation and their transport to the
gut and brain, causing the adverse neuropsychiatric and gastrointestinal
symptoms as a function of an endogenous form of hypervitaminosis A.”
Chloroquin
Chloroquin, used for more than 80 years as an
anti-malarial drug and more recently as a drug for auto-immune disease,
increases pH in Lysosomal compartments and inhibits autophagy in cancer
cells (57-58) “Daily uptake of clinically acceptable doses (less than
10mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the
survival of glioblastoma patients” Patients reeived o
ral chloroquine
at 150 mg/d for 12 months beginning on postoperative day 5 or placebo.
Median survival after surgery was 24 months for chloroquine-treated
patients and 11 months for controls.(66)
Upper left image: malaria mosquito engorged with blood.Courtesy wikimedia commons.
Dr Choi reports in 2014 that Chloroquin is an effective cancer stem cell agent.(57) See: “
Chloroquine eliminates cancer stem cells.” Chloroquin
was effective against pancreatic cancer cells/(60) and melanoma(61)
and breast cancer cell lines(62) via inhibition of autophagy.
“Chloroquin (CQ) may be one of the most effective and safe sensitizers for cancer therapies.
Taken together, it appears that the efficacy of conventional cancer
therapies can be dramatically enhanced if used in combination with CQ
and its analogs.”(65)
Ivermectin (Stromectol)
Ivermectin (Stromectol) is a potent blocker of the WNT pathway at low
doses. Ivermectin is an “astonishingly safe” anti-helminthic drug FDA
approved in the US for treatment of pediatric scabies. More than 200
million people take the drug globally for prevention or treatment of
parasitic disease. There is also extensive veterinary use in
pets.(79-89)
Left image: Ivermectin is HeartGuard for Dogs.
Ivermectin Patent for leukemia and lymphoma
Ivermectin was
patented in 2012 as
a treatment for hematological malignancy (including mantle cell
lymphoma).(91) Dr Simon Yu author of Accidental Cure, suggested that
Ivermectin use on the oncology wards could be justified by manufactured
concerns for occult parasitic infestation, thus labeling every oncology
patient with the diagnosis of
Ivermectin Deficiency Syndrome. (90)
Tracking WNT-TCF Perfectly
Dr Alice Melotti published her study on “
Ivermectin inhibition of WNT‐TCF pathway in cancer.”
in 2914 EMBO molecular medicine. (79) Dr Melotti used a transcriptional
reporter assay for TCF activity driven by ß-CATENIN to test a
collection of 1,040 drugs and small molecules (Microsource 1040
library). (See image below explaining TCF is the target gene for the
WNT pathway)
Only one agent perfectly tracked the gene expression profile induced
by blocking the TCF gene, and therefore blocks the WNT pathway. This is
Ivermectin, the anti-helmintic drug derived from the bacteria strain
Streptomyces avermitilis.(79) This has profound significance for
anti-cancer stem cell therapy, because blocking the WNT pathway is the
key to killing cancer stem cells.
The WNT PATHWAY- Key to Cancer Stem Cell Destruction
Cancer Cells Upregulated WNT Pathway- WNT ON – This is BAD
The WNT pathway controls embryonical devlopment and cell
proliferation, and is massively upregulated in cancer stem cells.
Inhibiting the WNT pathways kills cancer stem cells.(45)
Left Image:
WNT PAthway ON – β-catenin is NOT degraded.
The accumulated β-catenin enters the nucleus and activates the target genes such as LEF-1, c-myc and
Cyclin D1. Image
From : Chapter 3 Wnt/β-Catenin Signaling Pathway By Jae-Ik Han and Ki-Jeong Na. (44)
WNT Pathway OFF – This is GOOD – Beta Catenin Degraded
Left Image:
WNT OFF- In the absence of Wnt signals, a cellular complex degrades
β-catenin, so there is no entry into the nucleus, TCD/LEF is suppressed,
and no nuclear transcription of Cyclin D1 or other growth signals. (44)
Chapter 3 Wnt/β-Catenin Signaling Pathway By Jae-Ik Han and Ki-Jeong Na.
100-Fold Elevated Expression of WNT Target Genes in Stem Cells
Dr Rohit Mathur from MD Anderson reports in 2015 cancer Stem Cells
have elevated expression of Wnt target genes greater than 100-fold
compared with Mantle Cell Lymphoma non-stem cells (MCL non-ICs). The
authors also report that blocking the WNT pathway kills cancer stem
cells in
mantle cell lymphoma. (45) Dr Rohit Mathur says:
“The high rate of MCL relapse after initial apparent clinical remissions
achieved with conventional chemotherapy suggests incomplete elimination
of MCL cells and implicates a role for chemoresistant Mantle Cell
Lymphoma – Initiating Cells (stem cells called MCL-ICs ) in relapse.
Here we showed that MCL-ICs have functional properties of cancer stem
cells: high expression of ALDH, antioxidant enzymes,
chemoresistance-associated genes, and stem cell associated transcription
factors, while still retaining t(11;14) (q13; q32) and overexpression
of cyclin D1. Our analysis showed that MCL-ICs overexpress a subset of Wnt ligands and FZD receptors and that Wnt signaling is activated in MCL-ICs. Treatment
of primary MCL cells with Wnt inhibitors preferentially eliminated
MCL-ICs, which was not achieved with the current chemotherapy agents vincristine, doxorubicin, or even with the recently FDA-approved agent ibrutinib [28]. Burton tyrosine kinase (BTK) has been shown to be a negative regulator of Wnt signaling [29]. Therefore, it is not surprising that ibrutinib (a BTK inhibitor) probably resulted in inducing Wnt signaling rather than inhibiting it and thereby could not eliminate MCL-ICs.
Our results suggest that the inability of conventional chemotherapy to
kill MCL-ICs can be overcome by adding inhibitors of Wnt signaling”
The Glutamate-Cystine Antiporter -depleting glutathione in the cancer cell
Cancer stem cells have upregulated the production of glutathione
which protects them from oxidative damage and explains resistance to
chemotherpy. Blocking the cystine uptake transport (X ct) with
Azulfidine (sulfasalazine) depletes the cancer stem cell of glutathione
and kills the cancer stem cell.
Inhibiting Autophagy- Targeting the Lysosome -Chlorquin Mefloquin, PPI inhibitors
The anti-malaria drug, Chloroquin, accumulates in lysosomes and
inhibits autophagy, a necessary function in cancer stem cells. This
kills the cancer stem cell.
Inducing Autophagy
Resveratrol(Pterostilbene), Curcumin and Berberine induce autophagy cancer cell death (1B)
Salinomycin
Salinomycin, FDA approved in veterinary use in animals was found to
have striking activity against cancer stem cells. (43) However toxicity
to normal cells may represent a problem in human use.(43)
Common Antibiotics
Doxycyline and other commonly used antibiotics inhibit mitochondrial
biogenesis in cancer stem cells and may ultimately find their place in
routine use as anti-cancer stem cell agents. (73-78)
Conclusion: Targeting Cancer Stem Cells with
numerous non-toxic therapies and re-purposed drugs is now available.
Although not currently accepted by mainstream oncology, I predict many
of these non-toxic modalities will be incorporated into routine oncology
protocols.
Articles with related interest:
25 Cancer Stem Cell Killing Foods by Sayer Ji from GreenMedInfo
Artemisinin our Ultmate Anti-Cancer Weapon and other AntiCancer Botanicals
Cancer as a Metabolic Disease
Jeffrey Dach MD
Links and References
CD44 CANCER STEM CELLS 2015
1) Yan, Yongmin, Xiangsheng Zuo, and Daoyan Wei. “Concise review:
emerging role of CD44 in cancer stem cells: a promising biomarker and
therapeutic target.” Stem cells translational medicine 4.9 (2015):
1033-1043.
Emerging role of CD44 in cancer stem cells promising biomarker therapeutic target Yan Yongmin Stem cells 2015
Cancer Stem Cell Reviews
1A) Yu, Zuoren, et al. “
Cancer stem cells.” The international journal of biochemistry & cell biology 44.12 (2012): 2144-2151.
Excellent Review Article 2015
1B) Gali-Muhtasib, H., et al. “Cell death mechanisms of plant-derived
anticancer drugs: beyond apoptosis.” Apoptosis: an international
journal on programmed cell death 20.12 (2015): 1531-1562.
Cell Death Mechanisms Plant Anticancer Drugs Apoptosis Gali Muhtasib 2015
More than 3000 plant species have been reported to treat cancer and
about thirty plant-derived compounds have been isolated so far and have been tested in cancer clinical trials.
Recent studies have focused on the effects of plant-derived compounds on cell
cycle regulatory and apoptotic pathways [14, 15], yet little is known
about their effects on non-apoptotic pathways e.g. autophagy, mitotic
catastrophe, senescence leading to cell death, and programmed necrosis
or ‘‘necroptosis’’
The naturally occurring structural analogue to resveratrol,
pterostilbene, has also been reported to induce autophagy, cell cycle
arrest, and apoptosis in different
cancer types including bladder, breast, and leukemic cancer
1C) Scarpa, E. S., and P. Ninfali. “
Phytochemicals as Innovative Therapeutic Tools against Cancer Stem Cells.” International journal of molecular sciences 16.7 (2014): 15727-15742.
2016 Curcumin – Cancer Stem Cells
2) Huang, Yu-Ting, et al. “
Curcumin Induces Apoptosis of Colorectal Cancer Stem Cells by Coupling with CD44 Marker.” Journal of agricultural and food chemistry (2016).
This study investigated the effect of curcumin on colorectal cancer stem
cells (CCSCs) and its possible mechanism. Comparison of the metabolic
profiles of human adenomatous polyp (N = 61) and colorectal cancer (CRC)
(N = 57) tissue found statistically significant differences (p <
0.05) in their composition of adenosine monophosphate (AMP), adenine,
5′-methythioadenosine, 3-hydroxybutyric acid, prostaglandin E2,
threonine, and glutamine. Our cell culture model study found that
curcumin treatment (50 μM for 48 h) did indeed increase apoptosis of CRC
cells as well as of CCSCs, but at a significant level only in CD44+
cells. Further metabolic profile studies of the CRC, CD44+, and CD44–
cells indicated that curcumin treatment increased glyceraldehyde and
hydroxypropionic acid in CD44– cells but decreased glutamine content in
both curcumin-treated CRC and CD44+ cells. Based on our comparison of
the metabolic profiles of human tissues and cancer cells, we
suggest
that curcumin might couple with CD44 and that curcumin-CD44+ coupling
at the cell membrane might have some blocking effect on the transport of
glutamine into the cells, thus decreasing the glutamine content in the CD44+ cells and inducing apoptosis.
2015 Curcumin and EGCG !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!!!!!!!!!!
3) Chung, Seyung S., and Jaydutt V. Vadgama. “
Curcumin and Epigallocatechin Gallate Inhibit the Cancer Stem Cell Phenotype via Down-regulation of STAT3–NFκB Signaling.” Anticancer research 35.1 (2015): 39-46.
The
CD44+ cell population was also decreased
following curcumin and EGCG treatments. Our results suggest that the
final destination of STAT3 and NFκB signaling may be the CD44 expression
and accompanied by a cancer stem cell phenotype.
Conclusion: This study suggests that curcumin and EGCG function as
antitumor agents for suppressing breast CSCs. STAT3 and NFκB signaling
pathways could serve as targets for reducing CSCs leading to novel
targeted-therapy for treating breast cancer.
Curcumin – Mantle Cell Anti-cancer Effects
4) 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 Effective Against Four MCL cell lines
5) 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.
6) 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.
7) Singh, Amareshwar TK, et al. “
Curcumin nanodisk-induced apoptosis in mantle cell lymphoma.” Leukemia & lymphoma 52.8 (2011): 1537-1543.
8) 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.
9) Yallapu, Murali M., Meena Jaggi, and Subhash C. Chauhan. “
Curcumin nanomedicine: a road to cancer therapeutics.” Current pharmaceutical design 19.11 (2013): 1994.
Nice Review Article on Curcumin As Targeting Cancer Stem Cells
10)
Curcumin and Cancer Stem Cells Asymmetrical Effects AntiCancer Peter SORDILLO 2015 SORDILLO,
PETER P., and LAWRENCE HELSON. “Curcumin and Cancer Stem Cells:
Curcumin Ηas Asymmetrical Effects on Cancer and Normal Stem Cells.”
ANTICANCER RESEARCH 35 (2015): 599-614.
IL-6 (also known as interferon (IFN)-β2) is a multi-functional
cytokine involved in the immune and inflammatory response
and progression from inflammation to cancer. Increased IL-6
activity has been found in multiple cancers, including multiple
myeloma, as well as breast, colon and prostate carcinoma, and
IL-6 has been associated with decreased survival and more
aggressive disease in these patients
Furthermore, IL-6 has been shown to convert regular cancer cells to
CSCs in established breast and prostate cancer cell lines. One
mechanism by which curcumin targets CSCs is inhibition of IL-6 release
from cells, thus preventing CSC stimulation. Curcumin has been shown to
decrease IL-6 levels or inhibit IL-6 function in multiple experimental
systems.
IL-8 (CXCL8) is an important cytokine, which increases after tumor
cell death, stimulates CSCs and results in tumor regrowth and resistance
to chemotherapy
Curcumin is a potent inhibitor of IL-8 production, as well as of
numerous IL-8 cancer-promoting bio-activities. Curcumin was found to
reduce chronic non-bacterial prostatitis in rats by blocking IL-8
release
The Wnt signaling pathways regulate multiple processes during
embryonic development, as well as gene transcription, cell migration,
cell proliferation and tissue homeostasis in the adult organism
(103-107). These pathways occur in multiple species, including
drosophila, where much of the original work was done, as well as mice
and humans
Wnt signaling regulates levels of the protein β-catenin. Wnt
signaling is associated with a decrease in β-catenin phosphorylation, so
β-catenin accumulates and, in turn, stimulates the genes for VEGF,
cyclin D1 and c-Myc.
Aberrant Wnt signaling and excessive levels of β-catenin can result in carcinogenesis and uncontrolled cell proliferation.
Curcumin modulates Wnt signaling. Karkarala et al. have shown that
curcumin can inhibit Wnt signaling and the formation of mammospheres in
breast cancer cell lines, as well as in normal breast cell lines
Evidence indicates that curcumin can act at multiple points along the
Wnt pathway Like the Wnt pathways, the Notch pathway has been conserved
among species through evolution. The Notch signaling pathway plays a
critical role in regulating cell differentiation, cell proliferation and
apoptosis.
Curcumin acts to suppress tumor cells at multiple sites along the Notch pathway.
The question arises as to why curcumin does not seem to have the same
deleterious effects on normal stem cells (NSCs) as it does on CSCs.
Curcumin has been shown to have a much greater uptake by malignant cells
compared to normal cells.
Curcumin appears to shift the microenvironment around these cells to
one that is adverse to proliferation of CSCs, but conducive to NSCs. As
noted,
curcumin has been shown to suppress the release of proinflammatory
cytokines induction of CSC differentiation may be one of the ways curcumin depletes CSCs.
part of curcumin’s toxicity to CSCs involves suppression of molecular
abnormalities in the Wnt pathway, such as its inhibition of β-catenin
(122, 125-126). Curcumin has opposite effects on neural stem cells as it
stimulates neurogenesis.
—————————————————
11) Anticancer Drugs. 2014 Sep 16. [Epub ahead of print]
Curcumin
inhibits aerobic glycolysis and induces mitochondrial-mediated
apoptosis through hexokinase II in human colorectal cancer cells in
vitro.
Wang K1, Fan H, Chen Q, Ma G, Zhu M, Zhang X, Zhang Y, Yu J.
1aJiangsu Institute of Cancer Research bJiangsu Research Institute of Geriatrics, Nanjing, China.
Curcumin, the major pigment of the dietary spice turmeric, has the
potential for chemoprevention by promotion of apoptosis. Here, we
investigated the molecular mechanisms of curcumin in glycolytic
inhibition and apoptotic induction in human colorectal cancer HCT116 and
HT29 cells. On the one hand, curcumin
downregulated the expression and activity of hexokinase II
(HKII) in HCT116 and HT29 cells in a concentration-dependent manner,
but had little effect on the other key glycolytic enzymes (PFK, PGM, and
LDH).
On the other,
curcumin induced dissociation of HKII from the mitochondria, resulting in mitochondrial-mediated apoptosis.
Furthermore, the phosphorylation of mitochondrial HKII through AKT was
responsible for the curcumin-induced dissociation of HKII, which was
different from the mechanism of HKII inhibitor 3-BrPA. These results
have important implications for the metabolism reprogramming effect and
the susceptibility to curcumin-induced mitochondrial cytotoxicity
through the regulation of HKII, and provide a molecular basis for the
development of naturally compounds as novel anticancer agents for
colorectal carcinoma.
berberine synergy with curcumin
full free pdf
11A ) Balakrishna, Acharya, and M. Hemanth Kumar. “Evaluation of
synergetic anticancer activity of berberine and curcumin on different
models of A549, Hep-G2, MCF-7, Jurkat, and K562 cell lines.” BioMed
research international 2015 (2015).
In conclusion, we confirmed that the combination of Curcumin and
Berberine synergistically generates anticancer effects in A549, Hep-G2,
MCF-7, Jurkat, and K562 cells in vitro, possibly mediated by inducing
apoptosis. With regard to A549, Hep-G2, MCF-7, Jurkat, and K562
Curcurmin and Berberine are of extreme antitumor agents. The combination
of Curcumin and Berberine is a novel strategy that has potential in the
treatment of cancer patients.
The results had proven the synergetic anticancer activity of
Berberine with Curcumin inducing cell death greater percentage of
>77% when compared to pure Curcumin with <54% and pure Berberine
with <45% on average on all cell line models.
11B) Anticancer Res. 2015 Dec;35(12):6373-8.
Curcumin for the Treatment of Glioblastoma. Sordillo LA1, Sordillo PP1, Helson L2.
Glioblastoma multiforme is a highly aggressive primary cancer of the
brain associated with a poor prognosis. Modest increases in survival can
sometimes be achieved with the use of temozolomide and radiation
therapy after surgery, but second-line therapy after recurrence has a
limited efficacy. Curcumin has demonstrated promising results against
this form of cancer in experimental models. The reported activity of
curcumin against cancer stem cells, a major cause of glioblastoma
resistance to therapy, and its ability to augment the apoptotic effects
of ceramides, suggest it would have a synergistic effect with cytotoxic
chemotherapy agents currently used in second-line therapy, such as
lomustine.
Curcumin AML
11C) Rao, Jia, et al. “Curcumin reduces expression of Bcl-2, leading
to apoptosis in daunorubicin-insensitive CD34+ acute myeloid leukemia
cell lines and primary sorted CD34+ acute myeloid leukemia cells.” J
Transl Med 9.1 (2011): 71.
Curcumin reduces Bcl2 induces apoptosis in CD34pos acute myeloid leukemia cells Rao Jia 2011
Review – Many Natural Products That Target Cancer Stem Cells
12) 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)
Sulforaphane – Cancer Stem Cells – Breast CA
13) 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
14) 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
15) 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.
16) Wu, S., et al. “
Sulforaphane produces antidepressant-and anxiolytic-like effects in adult mice.” Behavioural brain research 301 (2015): 55.
17) Sestili, Piero, and Carmela Fimognari. “
Cytotoxic and Antitumor Activity of Sulforaphane: The Role of Reactive Oxygen Species.” BioMed Research International 2015 (2015).
18) 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).
19) Drug Deliv Transl Res. 2013 Apr 1; 3(2): 165–182.
Novel strategies targeting cancer stem cells through phytochemicals and their analogs. Prasad Dandawate, Subhash Padhye, Aamir Ahmad, and Fazlul H. Sarkarcorresponding author
——————————————–
Sulfasalazine
Cancer Stem Cells in gastric cancer- tumor cells evaluated before and after sulfasalazine for CD44.
Optimal dose of SSZ was considered as 8g/day
20) Shitara, Kohei, et al. “
Effect of sulfasalazine (SSZ) on cancer stem-like cells (CSCs) via inhibiting xCT signal pathway: Phase 1 study in patients with gastric cancer (EPOC 1205).” ASCO Annual Meeting Proceedings. Vol. 32. No. 15_suppl. 2014.
Effect of sulfasalazine (SSZ) on cancer stem-like cells (CSCs) via
inhibiting xCT signal pathway: Phase 1 study in patients with gastric
cancer (EPOC 1205).
2014 ASCO Annual Meeting Abstract Number: 2545 Citation: J Clin Oncol
32:5s, 2014 (suppl; abstr 2545) Author(s): Kohei Shitara et.al.
Background:
CD44 is an adhesion molecule expressed in
cancer stem-like cells (CSCs). Our group recently reported that CD44 splice variant (
CD44v) is expressed in CSCs and
interacts with xCT, a glutamate-cystine transporter, keeping high levels of the
intracellular reduced glutathione (GSH).
Thus, CSCs with a high expression of CD44v have an enhanced capacity
for GSH synthesis and defense against reactive oxygen species (ROS),
resulting in resistance to various therapeutic stresses.
Sulfasalazine
(SSZ) as an xCT inhibitor suppressed CD44v-dependent tumor growth and
increased sensitivity to cytotoxic drugs in vivo study.
Methods: A phase 1 dose escalation study in patients with advanced
gastric cancer was conducted to determine the optimal dose. SSZ was
given fourth-daily oral administration with 2 weeks as one cycle. A 3+3
escalation was used to evaluate a MTD. Tumor tissues were obtained pre-
and post SSZ administration to evaluate expression of CD44v and
intra-tumor level of GSH by immunohistochemistry and boron doped diamond
microelectrode, respectively.
Results:
Eleven patients were dosed from 8 g to 12 g/day;
median age: 71 years (61-78); median number of prior chemotherapies: 3
(1-4). There was two DLT of grade 3 anorexia and nausea among patients
who were treated with 12 g/day. One additional patients required
frequent dose interruption with grade 2 anorexia and nausea. Therefore
12g/day was judged as MTD. No DLT was observed among patients with
8g/day.
Patients with high CD44v expression patients achieved reduced
expression of CD44v after the administration of SSZ for 2 weeks as well
as decreased level of GSH.
The individual variability of SSZ exposure was explainable in terms
of the genotypes of ABCG2 and NAT2 which influence SSZ pharmacokinetics.
Conclusions: Optimal dose of SSZ was considered as 8g/day. Down
regulation of CD44v expression and decreased level of GSH migh be a
pharmacodynamic marker of drug-on-target effect and mode of action of
SSZ for CSCs, which warrants further investigation for combination with
chemotherapy or other targeting agents. Clinical trial information:
UMIN000010254.
stem cells – gastric cancer ccell line colon cancer cell line
full free pdf
21) 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 !!!
CD44 has recently been identified as one of the cell surface markers
associated with cancer stem cells (CSCs) in several types of tumor
CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter
Cells deficient in xCT or depleted of GSH have recently been found to
exhibit p38MAPK activation even at low levels of oxidative stress (Chen
et al., 2009; Sato et al., 2005), indicating that xCT-mediated cystine
transport for GSH
synthesis plays a key role in prevention of such stress signaling.
Sulfasalazine is a well-characterized specific inhibitor of
xCT-mediated cystine transport and has been shown to inhibit the growth,
invasion, and metastasis
of several types of cancer. sulfasalazine treatment stimulated the
phosphorylation of p38MAPK in HCT116 tumor cells in vivo. Finally, we
examined whether suppression of xCT function by sulfasalazine might
enhance the effect of the anticancer drug CDDP (Cis-Platin) on tumor
growth. The antitumor effect of CDDP at a low dose (2 mg/kg) was
significantly enhanced by treatment with sulfasalazine (Figure 8E),
suggesting that
sulfasalazine reduces the ROS defense capacity of cancer cells and sensitizes them to available chemotherapeutic drugs.
xCT is a component of a plasma membrane transporter (the xc system)
that mediates the cellular uptake of extracellular cystine in exchange
for intracellular glutamate a key role in GSH synthesis.
The activity of xCT-mediated cystine uptake in cancer cells
is highly associated with cell proliferation, chemoresistance, and tumor
growth
——————-
2013
sulfasalazine with 9-cis-retinoic acid (Panretin®, Alitretinoin, or
9-cis-retinoic acid, is a form of vitamin A. It is also used in medicine
as an antineoplastic (anti-cancer) agent developed by Ligand
Pharmaceuticals. It is a first generation retinoid. Ligand gained Food
and Drug Administration (FDA) approval for alitretinoin in February
1999.)
22)
http://cancerres.aacrjournals.org/content/73/6/1855.long
Yoshikawa, M., et al. “xCT inhibition depletes CD44v-expressing tumor
cells that are resistant to EGFR-targeted therapy in head and neck
squamous cell carcinoma.” Cancer research 73.6 (2013): 1855.
Sulfasalazine has been reported to inhibit not only the xCT-mediated cystine transport but also NF-κB signaling.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
!!!!!
Sulfasalazine – Inhibits Mantle Cell Lymphoma
23) 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.
MCL In vivo study in mice
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.
Sulfasalazine in Lymphoma
24) 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
25) 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.
The x c cystine glutamate antiporter as a potential therapeutic target for small-cell lung cancer_sulfasalazine Guan Cancer 2009
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
26) 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.
Potential
use of the anti-inflammatory drug, sulfasalazine, for targeted therapy
of pancreatic cancer Lo Gout Current Oncology 2010
Breast
27) 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
28) Doxsee, Daniel W., et al. “Sulfasalazine-induced cystine
starvation: Potential use for prostate cancer therapy.” The Prostate
67.2 (2007): 162-171.
Sulfasalazine Induced Cystine Starvation Prostate CancerTherapy Doxsee 2007
————————-
Toxicity sulphasalazine
29) Liedorp, M., A. E. Voskuyl, and BW Van Oosten. “
Axonal neuropathy with prolonged sulphasalazine use.” Clinical & Experimental Rheumatology 26.4 (2008): 671. Ann Med Interne (Paris). 2001 Jun;152(4):283-4. free pdf.
[Sulfasalazine neurotoxicity]. [Article in French] Chadenat ML1, Morelon
S, Dupont C, Dechy H, Raffin-Sanson ML, Dorra M, Rouveix E.
We report a case of seizures with
acute encephalopathy in a female patient under sulfasalazine treatment for polyarthritis.
Neurotoxicity secondary to sulfasalazine was suspected. This side effect has seldom been reported in the literature.
30) Clin Ter. 1997 Jan-Feb;148(1-2):7-13. [
Sulfasalazine: side effects and duration of therapy in patients with rheumatoid arthritis]. [Article in Italian] Mundo A1, Pedone V, Lamanna G, Cervini C.
Sulphasalazine (SSZ) is now recognised to be a useful agent in the management of rheumatoid arthritis (RA).
We studied SSZ toxicity (2 g/die) and duration of therapy in
102 patients with RA.
Adverse events occurred in 25.4% of all patients. In all patients the
reactions subsided on either discontinuation of the drug or decrease of
the dose. Gastrointestinal was the most common. At 5 years of follow-up
the percentage of patients treated with SSZ still on drug was 29%, the
inefficacy was 40% of the total drop-out.
—————————-
31) 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).
32) 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
33) Doxsee, Daniel W., et al. “
Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy.” The Prostate 67.2 (2007): 162-171.
34) 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.
35) 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.
36) 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
37) 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),
38) 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
———————————————————-
Mefloquin – AML cells and Progenitors (Stem Cells)
39) 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.
———————————————-
40) Blank
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Targeting progenitor cells Parthenolide (Feverfew)
41) 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
parthenolide AML depletion of glutathione
full free
42) 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
Targeting cancer stem cells – Salinomycin Pathenolide
43) 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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44) Chapter 3 Wnt/β-Catenin Signaling Pathway in Canine Skin
Melanoma and a Possibility as a Cancer Model for Human Skin Melanoma By
Jae-Ik Han and Ki-Jeong Na
45) 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
46) 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.
Sulforaphane
47) 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.
—————————– ———————————
Berberine – Berberine inhibits WNT Pathways
48) 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.
48A) Cell Physiol Biochem. 2013;32(5):1213-24.
Berberine induces apoptosis in p53-null leukemia cells by down-regulating XIAP at the post-transcriptional level. Liu J1, Zhang X, Liu A, Liu S, Zhang L, Wu B, Hu Q.
Berberine exerts anticancer activities both in vitro and in vivo
through different mechanisms. However, the underlying molecular
mechanisms of
berberine induced p53-independent apoptosis remain unclear.The
p53-null leukemia cell line EU-4 cells were exposed to berberine. Then
the cell viability and apoptosis were determined. Western blot and PCR
were employed to detect the expression of apoptosis related protein,
XIAP and MDM2. Small interfering RNA (siRNA) was applied to knock down
endogenous expression of MDM2 and XIAP.
RESULTS:Berberine induced p53-independent, XIAP-mediated apoptotic cell
death in p53-null leukemia cells. Treatment with berberine resulted in
suppression of XIAP protein in a dose- and time- dependent manner.
Berberine induced down-regulation of XIAP protein involving inhibition
of MDM2 expression and a proteasome-dependent pathway. Moreover,
inhibition of XIAP by berberine or siRNA increased the sensitivity of
leukemia cells to doxorubicin-induced apoptosis.
CONCLUSION: Our findings characterize the molecular mechanisms of
berberine-induced caspase activation and subsequent apoptosis, and
berberine may be a novel candidate inducer of apoptosis in leukemia
cells, which normally lack p53 expression.
Berberine
49) 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
50) Guamán Ortiz, Luis Miguel, et al. “Berberine, an epiphany against cancer.” Molecules 19.8 (2014): 12349-12367.
Epiphany Against Cancer
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.
Integrity of P53 relevant
In general,
the integrity of p53 is relevant because cells
with p53wt were found to be very sensitive to BBR, whereas cell lines
lacking functional p53 do not respond to BBR treatment.
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/ß-catenin pathway [56], which in normal cells is inactivated by ubiquitination and subsequent degradation of the ß-catenin protein,
Berberine Inhibits Cancer Stem Cells – Patent
51) 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.
————————————————————————–
Silibinin – Inhibits WNT pathway
full free pdf
52) 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.
53) 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
54) 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.
Pterostilbene – human lung adenocarcinoma
55) 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).
Chloroquin and Pterostilbene – autophagy inhibitor potentiated pterostilbene effect
56) 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.
——————————————————–
Chloroquin- Mefloquin
Cancer stem cells – chloroquin
57) Choi, Dong Soon, et al. “
Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.” Stem cells 32.9 (2014): 2309-2323.
Interestingly, CQ has been identified as a cancer stem cell targeting
agent for other aggressive cancers including breast cancer11, 12,
glioblastoma multiforme13, and chronic myeloid leukemia14. However, the
mechanism by which CQ affects the CD44+/CD24-/low CSCs remains unclear.
2016
58) Eur J Pharmacol. 2016 Jan 15;771:139-44. Epub 2015 Dec 11.
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.
Mefloquin – Gastric Cancer 2016
59) Liu, Yanwei, et al. “
Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway.” Biochemical and biophysical research communications (2016).
Deregulation of PI3K/Akt/mTOR pathway has been recently identified to
play a crucial role in the progress of human gastric cancer. In this
study, we show that mefloquine, a FDA-approved anti-malarial drug,
effectively targets human gastric cancer cells. Mefloquine potently
inhibits proliferation and induces apoptosis of a panel of human gastric
cancer cell lines, with EC50 ~
0.5-0.7 µM.
In two independent gastric cancer xenograft mouse models, mefloquine significantly inhibits growth of both tumors.
The combination of mefloquine with paclitaxel enhances the activity of
either drug alone in in vitro and in vivo. In addition, mefloquine
potently decreased phosphorylation of PI3K, Akt, mTOR and rS6.
Overexpression of constitutively active Akt significantly restored
mefloquine-mediated inhibition of mTOR phosphorylation and growth, and
induction of apoptosis, suggesting that mefloquine acts on gastric
cancer cells via suppressing PI3K/Akt/mTOR pathway. We further show that
mefloquine-mediated inhibition of Akt/mTOR singaling is
phosphatase-dependent as pretreatment with calyculin A does-dependently
reversed mefloquine-mediated inhibition of Akt/mTOR phosphorylation.
Since
mefloquine is already available for clinic use, these results suggest
that it is a useful addition to the treatment armamentarium for gastric
cancer.
pancreatic CA chloroquin
full pdf
60) Frieboes, Hermann B., et al. “Chloroquine-Mediated Cell Death in
Metastatic Pancreatic Adenocarcinoma Through Inhibition of Autophagy.”
JOP. Journal of the Pancreas 15.2 (2014): 189-197.
Chloroquine Mediated Cell Death in Metastatic Pancreatic Adenocarcinoma Through Inhibition of Autophagy 2014 Hermann Frieboes
Melanoma-chloroquin
61) Egger, Michael E., et al. “
Inhibition of autophagy with chloroquine is effective in melanoma.” journal of surgical research 184.1 (2013): 274-281.
BACKGROUND: Cancer cells adapt to the stress resulting from accelerated
cell growth and a lack of nutrients by activation of the autophagy
pathway. Two proteins that allow cell growth in the face of metabolic
stress and hypoxia are hypoxia-inducible factor-1a (HIF-1a) and heat
shock protein 90 (Hsp 90). We hypothesize that chloroquine (CQ), an
antimalarial drug that
inhibits autophagosome function,
in combination with either echinomycin, a HIF-1a inhibitor, or
17-dimethylaminoethylamino-17-dimethoxygeldanamycin (17-DMAG), an Hsp 90
inhibitor, will result in cytotoxicity in melanoma.
MATERIALS AND METHODS:
Multiple human melanoma cell lines
(BRAF wild-type and mutant) were tested in vitro with CQ in combination
with echinomycin or 17-DMAG. These treatments were performed in hypoxic
(5% O2) and normoxic (18% O2) conditions. Mechanism of action was
determined through Western blot of autophagy-associated proteins HIF-1a
and Hsp 90.
RESULTS:
Chloroquine, echinomycin, and 17-DMAG each
induced cytotoxicity in multiple human melanoma cell lines, in both
normoxia and hypoxia. Chloroquine combined with echinomycin achieved
synergistic cytotoxicity under hypoxic conditions in multiple melanoma
cell lines (BRAF wild-type and mutant). Western blot analysis indicated
that echinomycin reduced HIF-1a levels, both alone and in combination
with CQ. Changes in LC3 flux indicated inhibition of autophagy at the
level of the autophagosome by CQ therapy.
CONCLUSIONS: Targeting autophagy with the antimalarial drug CQ may be
an effective cancer therapy in melanoma. Sensitivity to chloroquine is
independent of BRAF mutational status. Combining CQ with the HIF-1a
inhibitor echinomycin improves cytotoxicity in hypoxic conditions.
Breast Cancer cell line
62) Sharma, Natasha, et al. “
Inhibition of autophagy and induction of breast cancer cell death by mefloquine, an antimalarial agent.” Cancer Letters 326.2 (2012): 143-154.
Prostate Cancer
full free
63) Yan, Kun-Huang, et al. “
Mefloquine induces cell death in prostate cancer cells and provides a potential novel treatment strategy in vivo.” Oncology letters 5.5 (2013): 1567-1571.
Krudsood et al(7) reported that MQ caused a blood plasma concentration of
5,796 ng/ml (15.35 µM)
in a clinical study on Plasmodium falciparum-infected adults. Dow et
al(8) noted that higher blood levels of MQ were reached under
therapeutic regimens (2.1–23 µM) rather than in prophylaxis (3.8 mM)
(9,10).
Mefloquin in Lysosomes
64) Glaumann, Hans, Anne-Marie Motakefi, and Helena Jansson. “
Intracellular distribution and effect of the antimalarial drug mefloquine on lysosomes of rat liver.” Liver 12.4 (1992): 183-190.
Abstract: Mefloquine was administered in a single dose (
1–30 mg/100 g)
to rats in order to study its subcellular distribution and effects on
rat liver lysosomal structure and function. Subcellular fractionation
showed a significant enrichment of
mefloquine in lysosomes.
Even repeated administration of mefloquine did not affect the levels of
cytochrome-P-450 or its reductase, indicating, although not proving,
that it is not metabolized by this mono-oxygenase system. Mefloquine
caused an
expansion of the lysosomal apparatus,
earliest seen by 24 h and lasting for some 7 days.
Initially, cytoplasmic constituents were seen inside the lysosomes.
Later, the lysosomes harboured myelin-like figures (multilamellar
bodies) disappearing after 7–10 days. The proteolytic and lipolytic
capacity was assessed in isolated lysosomes. Mefloquine caused increased
protein degradation but decreased breakdown of lipids. Concomitantly,
all
five major phospholipids (phosphatidyl-choline, -ethanolamine,
-inositol, -serine and sphingomyelin) increased in the lysosomes. It is concluded that: (1)
mefloquine
is a lysosomotropic drug that accumulates in lysosomes; (2) mefloquine
impairs lipid degradation with ensuing accumulation of lipids in
lysosomes; and (3) lysosomal trapping explains the high volume
distribution of mefloquine.
chloroquin
65) Eur J Pharmacol. 2009 Dec 25;625(1-3):220-33.
Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Solomon VR1, Lee H.
Chloroquine (CQ), N’-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely
used as an effective and safe anti-malarial and anti-rheumatoid agent.
CQ was discovered 1934 as “Resochin” by Andersag and co-workers at the
Bayer laboratories. Ironically, CQ was initially ignored for a decade
because it was considered too toxic to use in humans. CQ was
“re-discovered” during World War II in the United States in the course
of anti-malarial drug development. The US government-sponsored clinical
trials during this period showed unequivocally that CQ has a significant
therapeutic value as an anti-malarial drug. Consequently, CQ was
introduced into clinical practice in 1947 for the prophylaxis treatment
of malaria (Plasmodium vivax, ovale and malariae).
CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an
anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus
and amoebic hepatitis. More recently, CQ has been studied for its
potential as an enhancing agent in cancer therapies. Accumulating lines
of evidence now suggest that CQ can effectively sensitize cell-killing
effects by ionizing radiation and chemotherapeutic agents in a
cancer-specific manner. The
lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed,
CQ may be one of the most effective and safe sensitizers for cancer therapies.
Taken together, it appears that the efficacy of conventional cancer
therapies can be dramatically enhanced if used in combination with CQ
and its analogs.
Randomized human trial chloroquin prolonged survival in Glioblastoma.
full free pdf
66) Ann Intern Med. 2006 Mar 7;144(5):337-43. Adding chloroquine to
conventional treatment for glioblastoma multiforme: a randomized,
double-blind, placebo-controlled trial. Sotelo J1, Briceño E,
López-González MA.
Adding Chloroquine to Conventional Treatment for Glioblastoma Multiforme Sotelo Julio 2006
Malignant cell clones resistant to chemotherapy and radiotherapy
frequently lead to treatment failure in patients with glioblastoma
multiforme. Preliminary studies suggest that adding chloroquine to
conventional therapy may improve treatment outcomes.
OBJECTIVE: To examine the effect of adding chloroquine to conventional therapy for glioblastoma multiforme.
DESIGN: Randomized, double-blind, placebo-controlled trial.
SETTING: National Institute of Neurology and Neurosurgery of Mexico.
PATIENTS: 30 patients with surgically confirmed glioblastoma confined to
1 cerebral hemisphere, with a Karnofsky performance score greater than
70, no comorbid disease, and age younger than 60 years.
INTERVENTIONS:
Oral chloroquine at 150 mg/d for 12 months beginning on postoperative day 5 or placebo. All patients received conventional chemotherapy and radiotherapy.
MEASUREMENTS: Primary outcome was survival after surgery; surviving
patients were followed up to October 2005. Periodic evaluation using the
Karnofsky scale and imaging studies, as well as hematologic tests and
ophthalmologic examinations, was done in all patients.
RESULTS:
Median survival after surgery was 24 months for chloroquine-treated patients and 11 months for controls.
At the end of the observation period, 6 patients treated with
chloroquine had survived 59, 45, 30, 27, 27, and 20 months,
respectively; 3 patients from the control group had survived 32, 25, and
22 months, respectively. Although not statistically significantly
different, the rate of death with time was approximately half as large
in patients receiving chloroquine as in patients receiving placebo
(hazard ratio, 0.52 [95% CI, 0.21 to 1.26]; P = 0.139).
LIMITATIONS: The observed advantage of chloroquine may be due to chance;
differences in pretreatment characteristics and conventional treatment
regimens could not be adjusted for because of the small sample size.
CONCLUSIONS: Chloroquine may improve mid-term survival when given in
addition to conventional therapy for glioblastoma multiforme. These
results suggest that larger, more definitive studies of chloroquine as
adjuvant therapy for glioblastoma are warranted.
67) 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.
——————————————————————————-
Mefloquine – AML-stem cells killing Acute Myeloid Leukemia
2014
68) Zhang, Hui, Hai Fang, and Kankan Wang. “
Reactive oxygen species in eradicating acute myeloid leukemic stem cells.” Stem Cell Investigation 1.6 (2014).
Mefloquine – AML-stem cells killing
Most recently, Sukhai et al. an antimalarial agent called
‘mefloquine’ for its capacity in targeting newly AML-stem cells (32).
This study reveals a previously unappreciated mechanism for
AML-stem cells killing.
Mefloquine is able to disrupt lysosome integrity releasing hydrolases,
lipases, proteases and cathepsins. This disruption subsequently
increases the levels of ROS and triggers death of AML cells and stem
cells in a caspase-independent manner. Mefloquine is widely used for
malaria therapy and chemoprevention, its clinical safety has been
already characterized in large cohorts of clinical trials. Its AML
targeting efficacy will be next for evaluation.
Fenretinide Vit A –Also from Zhang, Hui,
Stem Cell Investigation 1.6 (2014).
Fenretinide is a well-tolerated vitamin A derivative that lacks a
carboxyl functional group likely necessary for retinoid receptor
activity. Our most recent study has shown that it is capable of
eradicating LSCs but not normal hematopoietic progenitor/stem cells, at physiologically achievable concentrations (5 µM).
Fenretinide-induced AML-stem cells death is associated with the rapid
generation of ROS, induction of genes responsible for stress responses
and apoptosis, and repression of genes involved in NF-?B and Wnt
signaling (34). Though there is no clinical trial ongoing for AML
treatment,
fenretinide has been verified its safety and low
toxicity in phase II-III clinical trials for solid tumors such as small
cell lung cancer, breast cancer and prostate cancer (82-85).
Moreover, via bioinformatics analysis we have observed that fenretinide
down-regulated genes are significantly correlated with genes related to a
poor prognosis/relpase of AML.
We anticipate that fenretinide is a potent AML-stem cells targeting candidate in the treatment of AML.
Parthenolide (PTL) and dimethylaminoparthenolide (DMAPT)
PTL is a naturally occurring small molecule that has been evaluated
for in vitro and in vivo efficacy on AML progenitor and stem cell
populations. However, low soluble feature makes its pharmacologic
potential less attractive. Instead, DMAPT, a dimethylamino analog of
PTL, demonstrates 1,000-fold greater solubility in water than PTL. Both
of DMAPT and PTL show similar efficacy on AML-stem cells through the
similar molecular mechanisms, including the elevated ROS, p53 activation
and NF-?B inactivation. Canine xenograft experiments, an equivalent to
phase I clinical trials, show that the pharmacologic properties of DMAPT
are superior to PTL (26,27). These data call for further studies on
clinical safety and translational efficacy of DMAPT/PTL in AML
treatment.
Mefloquin thioridazine (Mellaril) – AML cell line
69) Sachlos, Eleftherios, et al. “
Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.” Cell 149.6 (2012): 1284-1297.
compounds that induce differentiation can be identified based on the
reduction of GFP intensity in neoplastic hPSC reporter lines and could
be exploited for chemical screening.
This hPSC-screening platform was validated by using an assembled
library of 51 defined compounds with established stem cell and
anticancer activity
Compounds that can induce differentiation of neoplastic hPSCs are
potential anticancer candidates. the ideal compound should only
differentiate neoplastic hPSCs while not affecting normal hPSCs. we
extended our tests to chemical libraries composed of
590 well-established annotated compounds from the NIH Clinical Collection and Canadian Compound Collection
11 compounds were identified to induce differentiation as indicated
by a reduction in both GFP percentage residual activity (%RA) and
Hoechst %RA (Figures 2B and 2C). Four of these compounds (indatraline,
thioridazine, azathioprine, and
mefloquine) were identified as candidate compounds based on clustering and levels of Hoechst %RA in excess of 30%.
Only thioridazine and
mefloquine were found to possess EC50 values
lower than the 10 µM target threshold
At both 1 µM and 10 µM salinomycin reduced AML-blast CFU potential
(Figure 3J) but also reduced HSPC CFU potential over all doses tested
(Figure 3I), indicative of nonspecific toxicity in the hematopoietic
system.
In contrast, mefloquine and thioridazine reduced
AML-blast CFU formation (Figure 3J) while having little effect on HSPC
CFU potential (Figure 3I) and multilineage composition (Figure S3D), indicating that
mefloquine and thioridazine do not alter normal hematopoiesis.
Alternatively, the combination of thioridazine at 10 µM with AraC at
100 nM demonstrates almost complete elimination of AML-blast-CFUs while
preserving HSPC function (Figure 7F), suggesting that these specified
concentrations can induce remission and prevent relapse of AML in
patients. Collectively, these data show the synergistic benefit of
combining an anti-LSC agent (thioridazine) with an antiproliferative
agent (AraC) currently used as a single first-line treatment for human
AML and to targeting CSCs in addition to other cells in the leukemogenic
hierarchy. This combined effect with thioridazine is likely to have
significant benefit to AML patients as it can reduce the severe
cytotoxic effects associated with high-dose AraC therapy, as illustrated
in
————————————————————
Mefloquin Patent 2002
70)
Treatment of cancer with mefloquine, its purified enantiomers, and mefloquine analogs US 20030216426 A1
Regents Of The University Of California
Cancers, particularly solid tumors (e.g., breast, colon and ovarian
cancers) and cancers of the hematologic system, e.g., hemopoietic
cancers such as leukemias, lymphomas or myelomas, are treated by
administration of a therapeutically effective amount of a compound
having the formula (I):
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71) blank
72) blank
Antibiotics Eradicate Cancer Stem Cells
2015 OncoTarget
73) Lamb, Rebecca, et al. “Antibiotics that target mitochondria
effectively eradicate cancer stem cells, across multiple tumor types:
Treating cancer like an infectious disease.”
Lamb Rebecca Antibiotics that target mitochondria effectively eradicate cancer stem cells 2015 OncoTarget
Finally, recent clinical trials with doxycycline and azithromycin
(intended to target cancer-associated infections, but not cancer cells)
have already shown positive therapeutic effects in cancer patients,
although their ability to eradicate cancer stem cells was not yet
appreciated.
Doxycycline for Lymphoma
2015
74) Ann Hematol. 2015 Apr;94(4):575-81.
Long-term
outcomes of first-line treatment with doxycycline in patients with
previously untreated ocular adnexal marginal zone B cell lymphoma.
Han JJ1, Kim TM, Jeon YK, Kim MK, Khwarg SI, Kim CW, Kim IH, Heo DS.
Author information 1Department of Internal Medicine, Seoul National
University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South
Korea.
Ocular adnexal lymphoma (OAL) has been associated with Chlamydophila
psittaci infection, for which doxycycline has been suggested as a
treatment option. We conducted this study to evaluate the long-term
results of first-line doxycycline treatment in patients with OAL. Ninety
patients withhistologically confirmed OAL with marginal zone B cell
lymphoma were enrolled. Each patient received one or two cycles of
doxycycline (100 mg bid) for 3 weeks. After a median follow-up period of
40.5 months (8-85), the 5-year progression-free survival (PFS) rate was
60.9 %. All patients were alive at the last follow-up date. Thirty-one
patients (34 %) showed local treatment failure without systemic spread.
However, PFS rate in these patients was 100 % after salvage chemotherapy
and/or radiotherapy.
PFS was independently predicted in multivariate analysis by the
tumor-node-metastasis (TNM) staging (hazard ratio [HR], 4.35; 95 %
confidence interval [CI], 2.03-9.32; P < 0.001) and number of cycles
of doxycycline (HR, 0.31; 95 % CI, 0.14-0.69; P = 0.004). No serious
adverse event was reported during doxycycline therapy. In conclusion,
first-line doxycycline therapy was effective and safe.
Patients who failed to respond to doxycycline therapy were
successfully salvaged with chemotherapy and/or radiotherapy without
compromising long-term outcomes. Patients with T1N0M0 disease could be
considered good candidates for first-line doxycycline.
2015
13 patients antibiotics alone for gastric lymphoma – HP eradication regimen
75) Ann Hematol. 2015 Jun;94(6):969-73. doi: 10.1007/s00277-014-2298-3. Epub 2015 Jan 13.
Antibiotic treatment as sole management of Helicobacter pylori-negative
gastric MALT lymphoma: a single center experience with prolonged
follow-up. Raderer M1, Wöhrer S, Kiesewetter B, Dolak W, Lagler H, Wotherspoon A, Muellauer L, Chott A.
Relatively little is known about the long-term outcome of patients with
Helicobacter pylori (HP)-negative gastric lymphoma
of mucosa-associated lymphoid tissue (MALT lymphoma) with antibiotic
therapy as sole management. We have analyzed all patients with
HP-negative gastric MALT lymphoma undergoing antibiotic therapy as sole
management of their disease. HP negativity was defined as negative
histology, breath test and serology, and response to treatment, survival
and long-term outcome was assessed together with clinico-pathological
characteristics including t(11; 18) (q21; q21) translocation. Out of 97
patients with gastric MALT lymphoma, 24 were HP-negative, and
13 (5 females and 8 males) underwent only antibiotic management for initial therapy.
Eight had stage I and five were found to have stage II disease, with
three patients suffering from an underlying autoimmune disease.
Antibiotic therapy consisted of standard HP eradication regimens
consisting of clarithromycin in all patients, along with metronidazole
in seven and amoxicillin in six plus a proton-pump inhibitor. After a
median follow-up of 95 months (42-, 181+), 12/13 patients are alive. Six
patients with stage I disease achieved an objective response (five
complete (CR) and one partial remission, 46 %), four had stable disease
(lasting 11-27 months), and three progressed. All patients with stable
disease received chemotherapy, but only one patient due to clear cut
progression. One patient relapsed 23 months after initial CR, and
achieved a second CR with antibiotics now lasting 87 months. These
results indicate that a relevant percentage of patients with HP-negative
gastric MALT lymphoma may benefit from antibiotic therapy and do not
require additional oncological therapies. Our data suggest that the
remissions seen in these patients might be durable as evidenced by
prolonged follow-up in our series.
2013
76) Kiesewetter, Barbara, and Markus Raderer. “
Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature.” Blood 122.8 (2013): 1350-1357.
A single course of oral doxycycline at a dose of 100 mg given twice a
day for 3 weeks was the most popular regimen and was used by most
investigators.14⇓⇓-17,19⇓⇓-22 By contrast, Kim and coworkers19 added a
second course after an interval of 3 weeks for patients with residual
eye-related symptoms after the initial cycle. The activity of a 6-month
oral application of 500 mg clarithromycin twice a day was assessed in an
Italian pilot study,18 assuming potential additional direct anticancer
effects of macrolide antibiotics through changes in apoptotic mechanisms
of tumor cells. In addition, 1 patient received HP eradication as
first-line treatment of OAML. CR was achieved in 23 patients (18%) out
of the collective of all 131 patients reported. Thirty-six (27%) had a
PR
2006
77) Ferreri, Andrés JM, et al. “
Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial.” Journal of the National Cancer Institute 98.19 (2006):1375-1382.
Background: An association between ocular adnexal MALT lymphoma (OAL)
and Chlamydia psittaci (Cp) infection has been proposed, and recent
reports suggest that doxycycline treatment causes tumor regression in
patients with Cp-related OAL. The effectiveness of doxycycline treatment
in Cp-negative OAL has not been tested. Methods: In a prospective
trial, 27 OAL patients (15 newly diagnosed and 12 having experienced
relapse) were given a 3-week course of doxycycline therapy. Objective
lymphoma response was assessed by computerized tomography scans or
magnetic resonance imaging at 1, 3, and 6 months after the conclusion of
therapy and every 6 months during follow-up. Cp infection in patients
was determined by touchdown enzyme time-release polymerase chain
reaction (TETR-PCR). Statistical tests were two-sided. Results: Eleven
patients were Cp DNA–positive and 16 were Cp DNA negative. Doxycycline
was well tolerated. At a median follow-up of 14 months, lymphoma
regression was complete in six patients, and a partial response (≥50%
reduction of all measurable lesions) was observed in seven patients
(overall response rate [complete and partial responses] = 48%).
Lymphoma regression was observed in both Cp DNA–positive patients
(seven of 11 experienced regression) and Cp DNA–negative patients (six
of 16 experienced regression) (64% versus 38%; P = .25, Fisher’s exact
test). The three patients with regional lymphadenopathies and three of
the five patients with bilateral disease achieved objective response. In
relapsed patients, response was observed both in previously irradiated
and nonirradiated patients. The 2-year failure-free survival rate among
the doxycycline- treated patients was 66% (95% confidence interval = 54
to 78), and 20 of the 27 patients were progression free. Conclusions:
Doxycycline is a fast, safe, and active therapy for Cp DNA–positive OAL
that was effective even in patients with multiple failures involving
previously irradiated areas or regional lymphadenopathies. The responses
observed in PCR-negative OAL may suggest a need for development of more
sensitive methods for Cp detection and investigation of the potential
role of other doxycycline-sensitive bacteria.
Ferreri et al conducted a prospective phase 2 clinical trial of 27
patients (15 newly diagnosed and 12 relapsed) with OAML, using
doxycycline 100 mg orally twice daily for 3 weeks. Partial or complete
lymphoma regression after antibiotic therapy was observed in 7 of 11
Cp-positive and 6 of 16 Cp-negative patients, with an overall response
rate of 48%. The 2-year failure-free survival rate among patients
treated with doxycycline was 66%
Abramson et al84 treated 3 patients with biopsy-proven conjunctival
MALT lymphoma with antibiotic therapy, resulting in 2 complete
remissions and 1 partial response.
Husain et al43 conducted a meta-analysis, identifying 4 studies with a total of 42 patients who had
been treated with oral doxycycline.
———————————-
full free pdf
78) Husain, Amina, et al. “Meta–analyses of the association between
Chlamydia psittaci and ocular adnexal lymphoma and the response of
ocular adnexal lymphoma to antibiotics.” Cancer 110.4 (2007): 809-815.
Abramson DH, Rollins I, Coleman M.
Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Am J Ophthalmol. 2005;140:729–730. Am J Ophthalmol. 2005 Oct;140(4):729-30.
Periocular mucosa-associated lymphoid/low grade lymphomas: treatment with antibiotics. Abramson DH1, Rollins I, Coleman M.
To report on the treatment of primary mucosa-associated lymphoid
tumors (MALT)/low grade lymphomas of the conjunctiva/orbit treated
solely with systemic antibiotics. DESIGN: Retrospective interventional
case series.
METHODS: Three adult patients with biopsy/marker proven MALT lymphomas
of the conjunctiva/orbit were treated with systemic antibiotics and
followed for signs of local or systemic relapse.
RESULTS: All three patients showed a response to antibiotics based on
clinical, ultrasonographic, and MRI/CT imaging studies. Two patients
have had complete remissions (42 months follow-up) and one a partial
remission (18 months). No systemic relapses have occurred.
CONCLUSION:
MALT/low grade lymphomas of the conjunctiva/orbit respond to systemic antibiotic therapy and may have complete remissions.
Ivermectin
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Ivermectin inhibits WNT-TCF pathway
Ivermectin – WNT pathway
79) 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.
Ivermectin used 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.
Constitutive activation of canonical WNT-TCF signaling is implicated
in multiple diseases, including intestine and lung cancers, but there
are no WNT-TCF antagonists in clinical use. We have performed a
repositioning screen for WNT-TCF response blockers aiming to
recapitulate the genetic blockade afforded by dominant-negative TCF. We
report that Ivermectin inhibits the expression of WNT-TCF targets,
mimicking dnTCF, and that its low concentration effects are rescued by
direct activation by TCFVP16. Ivermectin inhibits the proliferation and
increases apoptosis of various human cancer types. It represses the
levels of C-terminal ß-CATENIN phosphoforms and of CYCLIN D1 in an
okadaic acid-sensitive manner, indicating its action involves protein
phosphatases.In vivo, Ivermectin selectively inhibits TCF-dependent, but
not TCF-independent, xenograft growth without obvious side effects.
Analysis of single semi-synthetic derivatives highlights Selamectin,
urging its clinical testing and the exploration of the macrocyclic
lactone chemical space. Given that Ivermectin is a safe anti-parasitic
agent used by > 200 million people against river blindness, our
results suggest its additional use as a therapeutic WNT-TCF pathway
response blocker to treat WNT-TCF-dependent diseases including multiple
cancers.
Wingless/integrase-1 (WNT) signaling. The name Wnt was a portmanteau
of int and Wg and stands for “Wingless-related integration site. Other
cancers also show an active canonical WNT pathway; these include
carcinomas of the lung, stomach, cervix, endometrium, and lung as well
as melanomas and gliomas
We have used a transcriptional reporter assay for TCF activity driven
by APC-insensitive N’?ß-CATENIN, to test a collection of clinical-trial
tested small molecules (Microsource 1040 library). Of the 4 putative
antagonists, only one, 4B5 (Avermectin B1), perfectly tracked the gene
expression profile induced by dnTCF4. anti-helmintic agent Avermectin
B1, which belongs to the 16-membered Avermectin macrocyclic lactone
family derived fromStreptomyces avermitilis.
The drug is used in humans against insect and worm infections,
including river blindness caused by Onchocerca volvulus. The dominant
negative forms of TCF (dn-TCF) that can be used to block Wnt signaling
in the nucleus. 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.
Ivermectin Inhibits 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.
commercial form from the pharmacy, Stromectol™,
Selamectin, which scored as toxic in the primary screen at 10 µM, was ˜ tenfold more potent than ivermectin.
Here we report that Ivermectin (Campbellet al, 1983), an off-patent
drug approved for human use, and related macrocyclic lactones, have
WNT-TCF pathway response blocking and anti-cancer activities. Whereas
the exact molecular target for Ivermectin and Selamectin that affects
WNT-TCF responses remains to be identified, the present findings show
that
these drugs block WNT-TCF pathway responses, likely acting at the level of
ß-CATENIN/TCF function, affecting ß-CATENIN phosphorylation status.
Cell toxicity appears at doses greater (> 10 µM for 12 h
or longer or > 5 µM for 48 h or longer for Ivermectin) than those
required to block TCF responses and induce apoptosis.
This drug does not cross the blood–brain barrier.
Indications may include treatment for incurable
ß-CATENIN/TCF-dependent advanced and metastatic human tumors of the
lung, colon, endometrium, and other organs.
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.
————————————————————————-
80)
NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011
81) Chhaiya, Sunita B., et al. “IJBCP International Journal of Basic
& Clinical Pharmacology.” International Journal 2.6 (2013): 799.
Chhaiya, Sunita.
Ivermectin pharmacology and therapeutic applications Sunita Chhaiya 2012
82)
The Pharmacokinetics and Interactions of Ivermectin in Humans.
Canga, Aránzazu González, et al.”The pharmacokinetics and interactions
of ivermectin in humans—a mini-review.” The AAPS journal 10.1 (2008):
42-46.
Ivermectin is exceptionally potent, with effective dosages
levels that are
unusually low. In the treatment of onchocerciasis,
the optimal dose of ivermectin is 150 µg/kg, but the
frequency of administration is still controversial,
ranging from
150 µg/kg once to three times yearly. The optimal duration of
treatment has not been established (6).
It is effective in most patients with scabies after a single
oral dose of 200 µg/kg, but often the regimen involves two or three
repeated doses, separated by interval of 1 or 2 weeks (7).
prolonged prothrombin ratios were observed in 148 subjects given
ivermectin orally. Although no patients suffered bleeding complications,
factor II and VII levels were reduced in most of them, suggesting
interference with vitamin K
metabolism.
———————————————————–
Take Ivermectin with FOod every 4 days.
83) J Clin Pharmacol. 2002 Oct;42(10):1122-33.
Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. Guzzo CA1, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC.
Safety and pharmacokinetics (PK) of the antiparasitic drug
ivermectin, administered in higher and/or more frequent doses than
currently approved for human use, were evaluated in a double-blind,
placebo-controlled, dose escalation study. Subjects (n = 68) were
assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg
(three times a week) or 90 or 120 mg (single dose). The 30 mg panel
(range: 34 7-594 microg/kg) also received a single dose with food after a
1-week washout. Safety assessments addressed both known ivermectin CNS
effects and general toxicity. The primary safety endpoint was mydriasis,
accurately quantitated by pupillometry. Ivermectin was generally well
tolerated,
with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg.
All dose regimens had a mydriatic effect similar to placebo. Adverse
experiences were similar between ivermectin and placebo and did not
increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax
were generally dose proportional, with t(max) approximately 4 hours and
t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin
was 2.6 times higher when administered with food. Geometric mean AUC
ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses,
respectively, indicating that the accumulation of ivermectin given every
fourth day is minimal.
This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.
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84)
Editorial Commentary: Ivermectin as a Complementary Strategy to Kill Mosquitoes and Stop Malaria Transmission? Richard W. Steketee1 and Feiko O. ter Kuile2
Repeated doses of up to 800 µg/kg have been used in
the treatment of onchocerciasis [8–10]. Furthermore, earlier
dose-escalation studies with ivermectin have shown that
doses up
to 2000 µg/kg (ie, 5 times the highest US Food and Drug
Administration–approved dose) are well tolerated with no indication of
central nervous system or general toxicity [11]. Additional dosing during the third day of the ACT treatment (as done in this trial) or at day 7 (and perhaps at day 14)
—————————————————–
Ivermectin safely given incombination with Artemisinin Derivative Artemether
85)
Efficacy
and Safety of the Mosquitocidal Drug Ivermectin to Prevent Malaria
Transmission After Treatment: A Double-Blind, Randomized, Clinical Trial
André Lin Ouédraogo1,a, Guido J. H. Bastiaens2,a, Alfred B. Tiono1,
Wamdaogo M. Guelbéogo1, Kevin C. Kobylinski3,4, Alphonse Ouédraogo1,
Aïssata Barry1, Edith C. Bougouma1, Issa Nebie1, Maurice San Ouattara1,
Kjerstin H. W. Lanke2, Lawrence Fleckenstein5, Robert W. Sauerwein2,
Hannah C. Slater6, Thomas S. Churcher6, Sodiomon B. Sirima1, Chris
Drakeley7, and Teun Bousema2,7
Background.
Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission.
Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans.
Methods. In this double-blind, placebo-controlled trial, 120
asymptomatic Plasmodium falciparum parasite carriers were randomized to
receive
artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin
(AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was
performed 1, 3, and 7 days after initiation of treatment to determine
Anopheles gambiae and Anopheles funestus survival and infection rates.
Results. The
AL-IVM combination was well tolerated. IVM
resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1
day after IVM (P < .001). Day 7 IVM plasma levels were positively
associated with body mass index (r = 0.57, P < .001) and were higher
in female participants (P = .003), for whom An. gambiae mosquito
mortality was increased until 7 days after a single dose of IVM (hazard
rate ratio, 1.34 [95% confidence interval, 1.07–1.69]; P = .012).
Although we found no evidence that IVM reduced Plasmodium infection
rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1
and AL-IVM2 resulted in 27% and 35% reductions, respectively, in
estimated malaria transmission potential during the first week after
initiation of treatment.
Conclusions. We conclude that
IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes.
86) Chaccour, Carlos J., et al.
“Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination.” Malar J 12.153 (2013): 10-1186.
Recent publications have highlighted the likely benefit of
combining ivermectin with drugs such as artemisinin combination therapy (ACT). ACT is
highly effective in most malaria-endemic settings but does not prevent
malaria-transmission in the first weeks after treatment [53,54].
=====================================================
87)
Ivermectin Use in Scabies ROBERT
S. FAWCETT, M.D., M.S., York Hospital Family Practice Residency, York,
Pennsylvania. Am Fam Physician. 2003 Sep 15;68(6):1089-1092.
—————————————-
ivermectin cancer cell death
2015
88) 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.
——————————–
2004
89) Drinyaev, Victor A., et al. “
Antitumor effect of avermectins.” European journal of pharmacology 501.1 (2004): 19-23.
90)
Searching for Ivermectin Deficiency Syndrome by Dr Simon Yu author of Accidental Cure.
91) 2012
Patent for Ivermectin as treatment for hematologic malignancy (including
mantle cell lymphoma.) Use of synergistic combinations of an
avermectin and an antineoplastic compounds for the treatment of
hematological malignancies EP 2498785 A1 (text from WO2011054103A1)
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