Artemisinin our Ultimate Cancer Weapon a Gift from China
by Jeffrey Dach MD
Beating Colon Cancer with Artemisinin
Susan, a 56 year old house wife, noticed abdominal pain and change in
bowel habits. An X- Ray test revealed Susan has colon cancer (lower
left image), with a typical apple core appearance on barium enema.
Susan was sent to a colon cancer surgeon who told her she needed an
operation to remove the cancer from her colon.
Left image: Tu You You winner of 2015 Nobel Prize in Medicine Courtesy of China Daily News. This article is part one, for part two
click here.
Artemisinin Prospective Randomized Trial in Colon Cancer
Susan read in the newspaper about
Dorothy Bradshaw, a colon cancer patient who participated in a
clinical study with Dr. Sanjeev Krishna at St George University London in 2010.(71)
Dorothy took a new anti-cancer drug called Artesunate (an artemisinin
derivative) for two weeks before her colon resection to remove the
tumor. Five years later, she is alive and well. This randomized study
was done with 20 colon cancer patients awaiting surgery. Half received
the Artesunate pill for two weeks prior to surgery, and the other half a
placebo. Five years later, there were 6 cancer recurrences in the
placebo group, but only one in the Artesunate (Artemisinin) group. There
were
no deaths in the Artesenate group, compared to
three deaths in the placebo group.(70-71) I was very impressed by this.
Susan called me to ask if Artemisinin could improve her chances of beating cancer recurrence after surgery. I said to Susan,
“Artemisinin is our ultimate weapon against cancer, a gift from China”
Left Image Artemisin
in
chemical structure. Active portion of molecule is the endo-peroxide
bridge (red arrows) highly reactive oxygen bridge which reacts with the
iron in malaria organisms, and the iron in cancer cells.
Ridiculing Chinese Herbs
Back in the old days when I was hospital based physician, we took
lunch in the doctor’s dining room where conversation included amazement
and ridicule at the stories of patients who took Chinese herbs for their
medical condition. The surgeons had a good laugh, expressing amazement
that any intelligent American would choose to take a Chinese herb for a
medical condition.
Below image: Dr. Tu YouYou wins Nobel prize in Medicine 2015 for discovery of Artemisinin. Image Courtesy of IFLScience and China’s Daily .
Artemisinin – A Gift From The Chinese Government
Back
in the 1960’s during the Vietnam War, the North Vietnamese soldiers
succumbed to malaria in great numbers. This military issue prompted the
Chinese government to develop better and more effective anti-malarial
drugs. China enlisted the help of a young medical student named, Dr Tu
YouYou who began working. She uncovered an ancient Chinese medical
text in an archaeological excavation written by Ge Hong (281–340 AC),
which describes an herbal tea, sweet wormwood, to treat fevers and
chills. This sweet wormwood tea was later mentioned in the 1596 Chinese
Compendium by Li Shizen. Dr Tu Youyou ultimately isolated the active
molecule in the tea, called artemisinin (figure 1 above), an effective
anti-malaria drug, for which she received the 2015
Nobel prize in Medicine. Artemisinin
and derivatives like artesunate are now life saving malaria drugs used
by millions. Who’s laughing at Chinese Herbs Now?
Antimalarial Drugs are Also Anti-Cancer Drugs
Left
Upper Image: Artemisinin reacting with Heme courtesy of O’neill, et al Molecular Mechanism of Action of Artemisinine Debate ONeill 2010. (131)
Dr. Das reports in a 2015 article that Artemisinin (or derivatives)
are effective against 55 cancer cell lines with inhibitory effects
against pancreatic cancer, osteosarcoma, lung cancer, colon, melanoma,
breast, ovarian, prostate, central nervous system, lymphoma, leukemia
and renal cancer cells. (1)
The molecular mechanism by which artemisinin compounds serve as
effective anti-cancer agents can be found in its molecular structure,
the endo-peroxide bridge which reacts with the iron molecule. (
see figure 1 above)
Cancer Cells Contain Massive Amounts of Iron (Fe)
We can exploit key metabolic differences between cancer cells and
normal cells, to come up with ways to kill cancer cells, while leaving
normal cells unharmed as discussed in a previous article,
cancer as a metabolic disease. This is the targeted non-toxic approach to cancer treatment. One such key metabolic difference is the higher
Iron (Fe) content of cancer cells.
Left Image shows endo-peroxide bridge (oxygen) in Artemisinin (1) attaching to Heme iron (Fe) (2) courtesy of Robert et al, “Characterization of the alkylation product of heme by the antimalarial drug artemisinin.” (132)
Cancer Cells Contain Massive Amounts of Iron in Lysosomes
Cancer cells express high levels of the transferrin receptors for
internalizing iron (Fe) at a tremendous rate.(21) This is a useful
difference from normal cells. The cancer cells have a voracious
appetite for Iron, and contain massive quantities of iron compared to
normal cells. In addition, the transport mechanism for iron in cancer
cells, called transferrin receptors are massively up-regulated.(18) In
fact, a correlation between expression of transferrin membrane receptor
and Ki-67 (a marker of tumor proliferation) has also been
reported,(19) The more aggressive the tumor, the greater number of
transferring receptors. This difference in iron content and iron
transport is why artemisinin compounds kill cancer cells selectively
while sparing normal cells.
Addition of Iron Enhances Killing Effect of Artemisinin
Left image: Schematic of Hemoglobin Molecule with Central Fe (Red). This Fe is Iron in the center of Heme Molecule .Courtesy of wikimedia.
Since the anti-cancer effect of artemisinin relies on presence of
Iron in the cancer cell, its effects are up-regulated 1.5-10 fold by the
addition of iron, as you might expect.(20)
Fenton Reaction in Lysosomes – Ferroptosis
What are lysosomes? Lysosomes are the
cell organelles
which contain acid used for digestion and degradation of unwanted
intracellular debris and endocytosed bacteria and proteins. For
example, our white cells, called neutrophils, kill bacteria in our
blood stream by eating them. Once eaten, these unwanted proteins are
digested in lysosomes, The acid in the lysosome is produced by a
molecular machine called the “V-ATPase”, a molecular pump for acid
production. Lysosomes often accumulate large amounts of iron,
especially in cancer cells, which may then react with oxygen, called
Fenton reaction, causing release of hydroxyl radicals. This compromises
the lysosomal membrane with release of acid contents freely into the
cell cytosol initiating a form of cell death is called “
ferroptosis”
(53) (as opposed to apoptosis), as we will detail below. (5) In this
scenario, Artemisinin enters the cancer cell lysosomes, which already
contain iron as a degradation product from ferritin. The endoperoxide
oxygen bridge in artemisinin reacts with iron , the Fenton Reaction, and
hydroxyl radicals are produced. The diagram below illustrates the mode
of action of Artemisinin in the cancer cell.
Mode of Action of Artemisinin Cancer Cell Death from Yang et al.(6)
Figure 9E from Yang et al.
Artemisinin enters cancer cell along with iron loaded ferritin. Both
enter the lysosome which then triggers mitochondria reactive oxygen
species (ROS) and caspase 3 programmed cell death.(6)
Cancer Cell Killing Mechanism according to Yang et al:
Firstly Artemisinin (ART) accumulates in the lysosomes. Second, ART
increases lysosomal acidification, cathepsin enzyme activity, and
protein degradation via promoting lysosomal V-ATPase assembly. ART
induces autophagy, based on the observations that ART increased
autophagosomes formation and enhanced autophagic flux.
“We believe that this perinuclear clustering of lysosomes
is, in fact, an indication of autophagy induction. We observed
increase of mitochondrial ROS implicating lysosomal iron as a critical
mediator in ART-induced mitochondrial ROS production and cell death. It
is possible that enhanced lysosomal degradation of ferritin induced by
ART leads to the transient increase of cytosolic ferrous iron, which
then affects the mitochondria, leading to enhanced mitochondrial ROS
production.”(6)
BAF (bafilomycin A1), a lysosomal (V)-ATPase inhibitor, was able to effectively inhibit the cell death induced by ART .
“Ferritin
delivery and degradation in lysosomes is required for the toxicity of
ART. Therefore, lysosomal inhibitors significantly protect the cells
from ART-induced cell death via blockage of ferritin degradation.”(6)
Chloroquin inhibits Ferritin Degradation and Cell Death induced by ART
“In fact, we also found that chloroquine inhibited the ferritin degradation and cell death induced by ART as efficiently as BAF (data not shown).”
BAF is a lysosomal inhibitor which prevents artemisinin cell
death. DFO is iron chelator which inhibits cell death. NAC (N acetyl
cysteine inhibits ROS )inhibits cell death. Images courtesy of Yang,
Nai-Di, et al. (6) “Artesunate induces cell death in human cancer cells “
Lysosomal Clustering and Accumulation At Nucleus
When Artemisinin enters the cancer cell, it causes a peculiar
re-arrangement of the lysosomes and mitochondria in a pattern typical
for autophagy (the cell eats itself and dies) as reported by Dr Brady
(see below). This peri-nuclear clumping has also been observed in
experiments
which knock out KIF5B, the only microtubule motor protein associated
with the lysosomes. Therefore it has been speculated that the effect of
Artemisinin in the lysosome is to impair the microtube motor proteins.
This perinuclear clustering of organelles is a prelude to programmed
cell death.
Left image: Top Row are 
Untreated Breast Cancer Cells showing lysosomes (dark stained particles) dispersed throughout cells.
Bottom Row, Breast cancer cells treated with Artemisinin. Yellow
arrows point to peri-nucelar clustering of autophagosomes (lysosomes).
Images from Figure 3 courtesy of Hamacher-Brady, Anne, et al.(80)
“Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells
via Iron-catalyzed Lysosomal Reactive Oxygen Species Production.” J.
Biol. Chem 2011.286 (2010): 6587-6601.
Left
Image shows Breast Cancer Cells (Top row, yellow arrow) treated with
artemisinin and holotransferrin demonstrating clustering of mitochondria
(green) and lysosomes(red). Normal breast cells (lower row) show no
clustering effects. Images from Figure 9 courtesy of Hamacher-Brady,
Anne, et al.(80)
Dr Kundu reports in a 2015 article in Acta tropica that many
anti-malarial drugs serve as anti-cancer drugs and vice versa (22).
Curcumin, resveratrol,
pterostilbene,
allicin (from garlic) are among the many natural substances that work
together in synergy with Artemisinin. In addition, Artimisisin, and
derivatives, enhance the anti-cancer activity of most conventional
chemotherapy agents.(22)
Artemisinin Derivatives and Ferritin Tagging
Efficacy of Artimisinin may be impaired by poor absorption and
relatively low blood level. How can the potency and efficacy of
Artemisinin be increased ? Make a derivative such a artemether,
artesenuate. Derivatives are modified artemisinin compounds possessing
greater bio-availability and potency. Be careful here because greater
bio-availablity and potency may be associated with increased toxicity
which we will discuss below.
Transferrin Tagged Artemisinin
Another technique is to tag the Artemisin molecule with transferrin,
the Iron carrier protein. This combination had greater anti-cancer
potency see
Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Nakase. (83)
Other Anti-Cancer Treatments Work in Synergy
Firstly, intra-cellular iron is required for Artemisinin to kill the
cancer cell. Having the patient take an Iron supplement (such as Iron
bis-glycinate, Optferrin Pure Encapsulations) increases the effect of
the Artemisinin. However on should be careful to take the iron
supplement at a different time from the Artemisinin to avoid reacting
directly with the iron in the GI tract. Most Artemisinin
practitioners will use a schedule to allow “rest days”. The Artemisinin
is taken 14 days, and then take 4 days off. This is thought to
improve GI absorption.
Additional anti-cancer supplements work synergistally with artemisinin. These include
Vitamin D, Iodine (iodoral)
Berberine,
Curcumin (lipospheric) (24-29), Resveratrol,
Pterostilbene,
Allicin,
Melatonin,
Sulphoraphane, Butyrate and high dose vitamin C, fresh juicing with
organic carrots and organic beets, Lipo-Colostrum (Soveriegn Labs), a
good multivitamin (One Multi Pure Encapsulation) . (79)
Artemisinin-Curcumin Synergy
In a 2006
study
using malaria infected cultured RBC;s, the combination of artemisinin
with curcumin was found to synergize.(56) This combination showed
greater malaria killing activity than the individual compounds. The
molecular pathways were not elucidated. One might anticipate a
synergistic effect for this combination in killing cancer cells.
However, to my knowledge this has not yet been studied, and would be a
good topic for NIH funding for future research.(56)
Artemisinin – Allicin (Garlic) Synergy
Allicin,(diallyl thiosulfinate) the active ingredient in garlic, has
known anti-cancer effects. Allicin induces caspase mediated apoptosis in
lymphoma
and other cancers. Dr Jiang (see Left Image) reported in 2013 the
synergistic combination of Artesunate (artemisinin derivative) with
allicin had a heightened anti-cancer effect on osteosarcoma cell lines
in vitro and in vivo.(57) Left Image Fig 3B from Jiang showing
synergistic effect of combining Artesunate (an Artemisin derivative)
with Allicin. Bar Chart shows apoptosis levels after treating
Osteosarcoma cells (in culture) with Artesunate (green arrow), Allicin
(blue arrow) or combination of Artesunate and Allicin (Red Arrow). (57)
Dr Jiang also reported additional mouse tumor xenograft studies were
done, and these in-vivo studies also showed enhanced synergy for the
combination of Allicin and Artesunate. (57)
Platelet Inhibition
Allicin,and thiosulfinates, are
potent platelet-aggregation inhibitors
which can aggravate bleeding, so caution is advised when used with
other platelet inhibitors such as Feverfew, Aspirin, Vitamin E, Fish Oil
or ibrutinib (Imbruvica – Bruton’s-Kinase Inhibitor).
Synergy Artemisinin with Resveratrol
In
2014, Drs Li and Yang reported a synergistic effect of the combination
of Resveratrol with Artemisinin in Hepatoma (HepG2) and Cervical Cancer
(HeLa) cell lines. The combination significantly increased apoptosis and
necrosis of the two cancer cell lines. (58)
Left Image Bar Chart
from Li and Yang showing cancer cell death (apoptosis) after treatment
with Artemisinin (green arrow), Resveratrol (blue arrow) and the
Combination (red arrow) for two cancer cell lines (black and grey
bars).(58)
Although Pterostilbene was not used in this study, the Pterostilbene
is a derivative of Resveratrol, chemically similar with better
bioavailability, and I would therefore expect Pterostilebene to
demonstrate an even greater synergy with Artemisinin compared to
Resveratrol. A 2005 study by Dr Tolomeo showed the 3-Hydroxy
Pterostilbene to be 50-100 times stronger than Resveratrol in killing
multi-drug resistance leukemia cells. However, the plain pterostilbene
was the least toxic to normal hematopoetic cells. (59)
Synergy of Artemisinin with Butyrate (76, 122-128)
Dr
Lai reports in 2005 that the cancer cell killing effect of Artemisinin
is enhanced with the addition of butyrate, a short chain fatty
acid.(76) Their study used a lymphoblastic leukemia cell line, treated
with a combination of dihydroartimisin and butyrate.
Left Image Bar Chart courtesy of Dr Lai 2005, Cell Count after
treatment with Dihydroartemisinin(Green Arrow), after Butyrate (blue
Arrow), After Combination (Red Arrow)
In a 2007 report, Dr Pajak outlined the
molecular basis of anti-cancer effects of butyrate. (123)
Butyrate,
a small four-carbon chain fatty acid, is a normal product of large
bowel microbial fermentation of dietary fiber. Butyrate inhibits (HDAC)
histone deacetylase activity, allowing DNA binding of several
transcription factors which increases expression of proapoptotic genes,
and results in amplification of apoptotic pathways (programmed cell
suicide) in the cancer cell, while sparing normal cells.
In a 2013 report, Dr JK Fauser studied the anticancer effects of
butyrate and coconut oil (lauric acid) on a colon cancer cell line. Dr
Fauser reported butyrate induces apoptosis by:”
inhibiting
histone deacetylase activity, inducing cell cycle arrest, promoting
differentiation, activating NF-κB, downregulating α 2 β 1 , modifying
glucose availability, and inducing caspase activation in colon cancer
cell.” (125)
Dr Choi reported in a 2006 study on the anti-cancer effects of
butyrate on a leukemia cell line.(124) Dr Choi found that butyrate
induced apoptosis of human leukemic cells by inhibition of telomerase
activity. In addition,
butyrate served as a (HDAC) histone deacetylase inhibitor, resulting in dose-dependent
apoptosis associated with up-regulation in pro-apoptotic Bax
expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL.(124)
In a 2006
report
Dr Heider studied the effect of the HDAC, sodium butyrate, on three
Mantle Cell Lymphoma types. Dr Heider reported butyrate induced potent
programmed cell death (apoptosis) of all three Mantle Cell Lymphoma
types in a dose-dependent manner. (136)
Buy
Sodium Butyrate on Amazon.
Link to a review. A probiotic named
Clostridium butyricum is known to produce butyrate This is available from Japan in a product called
“Miyarisan” available on Amazon. It is also contained in
Advanced Orthomolecular Research AOR Probiotic 3.
Targeting (Progenitor) Cancer Stem Cells
Cytotoxic chemotherapy may be quite useful for controlling
hematologic cancers such as lymphoma and leukemia. Although highly
toxic, and frequently associated with adverse effects, these drugs may
induce complete remission (CR), with disappearance of tumor masses and
clearing of radionuclide activity on a follow up PET scans. In the more
aggressive cell types, relapse with metastatic disease is inevitable.
Relapse is thought caused by
cancer stem cells
(progenitor cells) which are dormant and not actively replicating.
These cancer stem cells are insensitive (resistant) to cytotoxic
chemotherapy which is not effective for non-replicating cells. (86-88)
Are there natural non-toxic targeted therapies which target cancer stem
cells?
Yes, and here they are a few of the many:
Berberine, Resveratrol, Vitamin D3, Curcumin, Feverfew, and Sulforaphane. (89-90) These are natural substances that target cancer stem cells as discussed by Dr Yanyan Li in his 2011
article : which also includes soy isoflavone, epigallocatechin-3-gallate, lycopene, piperine, and vitamin D3. (134)
FeverFew – Targeting Cancer Stem Cells – Depleting Glutathione
The well known anti-migraine botanical , Feverfew (parthenolide) has
been found to target the cancer stem cells.(74) The authors state:
“ Parthenolide preferentially targets
AML progenitor and stem cell populations….The molecular mechanism of
Parthenolide- with inhibition of nuclear factor κ B (NF-κB),
proapoptotic activation of p53, and increased reactive oxygen species (ROS).
On the basis of these findings, we propose that the activity of
Parthenolide triggers Cancer Stem Cell-specific apoptosis and as such
represents a potentially important new class of drugs for Cancer Stem
Cell-targeted therapy.”(74)
Feverfew (Parthenolide) is a widely used botanical which exerts
potent anti-cancer effects by blocking nuclear activation of Nuclear
Factor Kappa Beta (NFKB), and
depleting the cancer cell of glutathione,
rendering it sensitive to ROS (reactive oxygen species) which triggers
apoptotic pathways. (92-108) Parthenolide shares some similarities in
chemical structure with Artemisinin. One might speculate that the two
agents might work synergistically together with enhanced cancer cell
killing effects, and this would be a good topic for NIH funding and
future study. (92-108)
Sulforaphane – Targeting Cancer Stem Cells and Depleting Glutathione
The active ingredient in broccoli is sulforaphane, a widely used
nutritional supplement with no adverse effects. Sulforaphane has been
widely studied as an effective anti-cancer agent which targets cancer
stem cells and
depletes glutathione in the cancer cell, thus rending it more sensitive to oxidative damage.(109-115)
Dr Yanyan Li, et al reported in 2010 that sulforaphane eliminated
breast cancer stem cells in vivo in a mouse xenograft model. Tumor
bearing primary mice were treated with sulforaphane. The tumor cells
from the primary mice were then re-implanted into secondary mice,
showing no growth of tumor cells, indicating the cancer stem cells has
been eradicated. (112) I was impressed by this. A 2012
study
by Dr Rodova showed Sulforaphane is effective anti cancer treatment for
pancreatic cancer stem cells via blockade of hedgehog signalling.(135)
Other Re-Purposed Drugs that may Work with Artemisisin:
Sulfasalazine
(Asulfadine)- an old anti-inflammatory drug widely used in
rheumatology, inhibits the active transport of cystine into the cancer
cell. (39-46) (116-121)
When the cancer cell is deficient in cystine, it cannot make
glutathione, the intra-cellular anti-oxidant. Lack of anti-oxidant
protection leads directly to “ferroptosis” in cancer cell studies.(see
image at left).(39-46)
Left above image: schematic of sulfasalazine blocking cystine
uptake by cancer cell, thereby inducing Ferroptosis. Courtesy of Dixon
et al., “Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death ”. Cell, vol 149, pp. 1060‒1072 (2012).
Sulfasalazine has a long history of
use for inflammatory bowel disease and rheumatoid arthritis. Benefits are thought to arise from its ability to
suppress nuclear factor Kappa Beta.
Sulfasalazine is also a potent suppressor of lymphoma cells on the
basis of suppression of cystine uptake which impairs antioxidant
defense. Dr Gout found that sulfasalazine suppressed 90% of lymphoma
xenografts in mice, a remarkable finding. (41) In addition,
sulfasalazine inhibits growth of mantle cell lymphoma in a murine MCL
model as
reported by Dr Bebb in 2003 Blood.
Since “
Ferroptosis” is also seen when cancer cells are treated with Artemisinin, one might logically assume the two drugs
Artemisinin and Sulfasalazine
would be synergistic, augmenting cancer cell death. Unfortunately, the
appropriate cell culture studies (in-vitro or in-vivo) have not yet
been done. This would be a good study for NIH funding of further
research.(39-46)
Chloroquin
Hydroxychloroquine (Plaquenil) and Chloroquine (Avelan), are old
anti-malarial drugs. They serve as lysosomal inhibitors. (47-52)
Pretreatment with chloroquin augmented the cancer killing effect of
artemisinin in a 2014
cancer cell study by Dr Ganguli et al.
However, a prior cell study by Dr Hamacher-Brady, found that concurrent
chloroquin treatment (at the same time) as artemisinin impaired cancer
cell killing activity.(80) Dr Nai-Di Yang also found that Chloroquin
inhibited the effect of artemisinin in his study, similar to the
activity of the lysosomal V-ATP-ase inhibitor, Baflinomycin. See: Yang,
Nai-Di, et al. (6) “
Artesunate induces cell death in human cancer cells “
So, it is clear that simultaneous or concurrent use of chloroquin
together with Artemisinin should be avoided, as this inhibits the cell
killing effects. Rather, as suggested by
Dr Ganguli et al.,
it might be appropriate to use the chloroquin drug as a pre-treatment.
In other words, take the chloroquin during one of the OFF-DAYS when the
patient is
not taking the artemisinin. A typical
artemisinin schedule is 14 days on and 4 days off, (although this may
vary). So, taking the chloroquin during the days off would serve as a
pre-treatment for the next Artemisinin cycle as suggested by
Dr Ganguli et al.
Chloroquin and has a long track record of safety in
treatment of rheumatoid arthritis at a dosage of 250 mg daily for years. The most worrisome
toxicity
relates to ocular and macular toxicity at high doses over long periods
of time. The use of a small dose of 250 mg of chloroquin once a week
prior to the start of a 5 day course of artemisinin is considerably less
than usual chloroquin dosage for rheumatologic disease, and therefore
considered safe. Usual chloroquin dosage for travelers
prevention of malaria
is one 500 mg tablet once a week starting one week before departure,
and continuing for 4 weeks after returning. Although higher doses may
have retinal toxicity, typical prophylactic doses are
considered not harmful to the retina.
Sequential, and not concurrent, use of Chloroquin might ultimately
prove to be effective for augmenting the anti-cancer effect of
Artemisinin. I would like to see mouse xeno-graft tumor validation
studies of this combination. However, as far as I know, these types of
in-vivo studies have not been done. This would be a good subject for
NIH funding of future research.(47-52)
Mefloquin (Lariam)
Mefloquin was found to be superior to Chloroquin in a 2012
report by Dr Sharma who found Mefloquin caused cell death in breast cancer cell cultures. In a 1992
report
by Dr Glaumann, Mefloquin caused expansion of lysosomes in rat livers
starting at 24 hours after administration and lasting for 7 days. The
lysosomes later harbored multi-lamellar bodies which disappeared after
7-10 days.
Mefloquin – Acute Myelogenous Leukemia (17)
Dr M Sukhai et al. reported in their 2013 article “
Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.
Dr Sukhai screened a library of 100 on and off patent drugs for
activity against AML (acute luekemia). At the top of the list was
Ivermectin (see below), and the second most acive was the anti-malarial
drug mefloquin which selectively killed a panel of leukemia cells and
leukemia stem cells in mice.(17)
Mefloquin – Malaria Prophylaxis for Travelers
Mefloquin is
currently recommended
for malaria prophylaxis in travelers. Dosage is usually on 250 mg
tablet per week for a few weeks prior to the trip. Toxicity: There may
be neuro-psychiatric
symptoms of toxicity reported by some. Artemisinin has been used in combination with Chloroquin or Mefloquin for decades, however
long term use can result in neurotoxicity, so caution is advised.
Artemisinin Synergy with Other Chemotherapies – Rituximab
The anti-CD-20 monoclonal antibody, rituximab, has revolutionized the
treatment of lymphoma, by targeting the CD20 protein on B cell
membranes, and increasing response and survival rates. Artemisinin has
been given with rituximab with good synergism and increased anticancer
activity.
See: Sieber, Sebastian, et al. “Combination treatment of malignant B
cells using the anti-CD20 antibody rituximab and the anti-malarial
artesunate.” International journal of oncology 35.1 (2009): 149-158.
Combination treatment of malignant B cells Rituximab and Artesunate Sieber Sebastian Int j oncology 2009
Artemisinin Safety and Toxicity
A
case report
of elevated liver enzymes in an Artemisinin user was reported in 1999.
Therefore, it is prudent to monitor liver enzymes in patients on long
treatment. Neurotoxicity of the more potent artemisinin derivatives
has been reported in studies using animals (
dogs and mice.). Anecdotal reports of
cerebellar toxicity have been reported in humans. In spite of this, Artemisinin is remarkably safe as demonstrated in
this study
of 242 Vietnamese human subjects who showed no brain stem adverse
effects after multiple courses of artemisinin (or its derivatives) for
malaria treatment. Another study, looking at
post mortem neuropathology also found no evidence of neurotoxic effects.
Reproductive Toxicity of Artesunate: In a 2011 study by Dr Olumide and in a later 2014 study,
long term administration to mice of the more potent artemisinin
derivative, artesunate, induced reversible infertility, with reduced
sperm counts.
Cannabinoid Extracts Have Anti Cancer Activity – See my
previous article
on the use of cannabis extracts in treatment of cancer. Cannabis
extracts have a long history of beneficial use in chemotherapy patients
for relief of nausea, and increase appetite effects. There is also a
pain relief effect from cannabis extracts. Another unexpected benefit
is the anti-cancer effects of cannabis are substantial, especially in
Leukemia and Lymphoma cells which are specifically sensitive to cannabis
extracts as they express increased CB1 and CB2 cannabinoid receptors.
Numerous research studies show that Cannabinoid extracts and ligands
induce apoptosis (programmed cell death) in cancer cells via ceramide
accumulation. (30-38)
Is there synergism and augmentation of anti-cancer effects with
cannabis extracts and artemisinin compounds ? Taken in together
combination, would cannabis extracts increase the anti-cancer effect of
artemisinin ? This would be a good topic for NIH funding of future
research. My best guess is that future research studies will
demonstrate this is indeed the case.
Medicinal Use of Cannabis Extracts have been approved in 23 states so
far. If you reside in one of these states, then you may qualify as a
medicinal cannabis patient and may legally obtain medicinal cannabis
according to your specific state law. A reputable source for high
quality medical grade cannabis oil is
Mara Gordon of
Aunt Zelda’s Dispensary in San Fransisco, California. (note: I have no financial relationship with Aunt Zeldas) . For more on information, see my book on Amazon:
Cannabis Extracts in Medicine
Gleditsia sinensis – Korean thorn
This natural plant botanical has shown anticancer activity. Possible synergy with artemisinin might be explored. (60-61)
Ivermectin (62-68) (Stromectol for humans and Ivomec for Dogs)
The
2015 Nobel Prize in Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovery of Ivermectin,
the Wonder Drug From Japan, a well known anti-parasitic agent used to treat
“billons” of pets and livestock around the world. (62-68)
Left image : Ivermectin (HeartGuard) for dogs. Image Courtesy of All Four Paws .
In humans, Ivermectin is well known as treatment for Lice
(Pediculosis) and Scabies (Mites). Ivermectin also treats parasites
such as Nematodes, Onchocerciasis, Strongyloidiasis, Ascariasis,
cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis.
In 2010, Dr Sharmeen published his study. (62) He screened a long list of drugs looking for cytotoxicity to leukemia cells, and discovered
ivermectin induced
cell death at low micromolar concentrations in acute myeloid leukemia
cell lines, while sparing normal cells. He then studied three mouse
models of leukemia showing that tumor growth was delayed
“at drug concentrations that appear pharmacologically achievable“(62)
Dr Sharmeen reported ivermectin blocks the glutamate-gated chloride
channels, increases intracellular chloride ion concentrations and cell
size of leukemia cells. This causes plasma membrane hyperpolarization.
Ivermectin also increased (ROS) reactive oxygen species in cancer cells
functionally important for ivermectin-induced cell death. Finally,
ivermectin synergized with conventional chemotherapy agents, ARA-C
(cytarabine) and Adriamycin (anthracycline drug also known as
Daunorubicin) to increase ROS, reactive oxygen species production. (62)
Above
image: mechanism of Ivermectin induced caner cell death from Fig 7
Model of P2X4/P2X7/Pannexin-1-induced cancer cell death. Draganov 2015
Dr Dobrin Draganov
reported in 2015 that Ivermectin “
kills
mouse and human triple-negative breast cancer (TNBC) cells through
augmented P2X7-dependent purinergic signaling associated with caspase-1
and caspase-3 activation.” …”
also involved is the
recruitment and activation of T cells, macrophages and dendritic cells, a
form of immunomodulation and cancer immunotherapy.”
In 2014, Dr Alice Melotti reported that
Ivermectin inhibits the WNT‐TCF pathway in cancer cells.
further elucidating the molecular mechanism of cancer cell death.(130)
In a colon cancer cell model, Dr Melotti found Ivermectin effective at
micromolar concentrations against both tumor bulk as well as cancer stem
cells. The authors suggested ivermectin,”
might be useful as a
routine prophylactic agent, for instance, against colon cancer in
familial polyposis, or to prevent nascent cancer in the general aging
population.” (130) I was astonished by this statement.
Some aggressive cancers have a high relapse rate due to cancer stem
cells which are resistant to conventional chemotherapy. Targeting the
WNT pathway successfully eliminated cancer stem cells in a Mantle Cell
Lymphoma cell line.(133)
Cannabinoids also
inhibit cancer cells via the WNT-TCF signalling, so there may be some overlap in similar mechanisms. Interestingly, Lithium
stimulates hippocampal neurogeneisis through the WNT pathway.
Safety and Dosage of Ivermectin
About 200 million are currently taking Ivermectin as treatment/prevention of river blindness.
According to Dr.
Crump, Ivermectin is “astonishingly safe for human use.” He says
“Indeed,
it is such a safe drug, with minimal side effects, that it can be
administered by non-medical staff and even illiterate individuals in
remote rural communities,”
Dr Guzzo
reports
in 2002, no indication of associated CNS toxicity for Ivermectin doses
up to 10 times the highest FDA-approved dose of 200 microg/kg.(120 mg
single dose is 10 times the 12 mg recommended dose). There was better
absorption with higher plasma levels when the drug is taken with food.
Ivermectin
dosage for treatment of head lice (pediculosis)
is Two Tablets, each one given a week apart, tablet size is 200 mcg/kg
(12 mg tablet for a 60kg male).(137) As much as 11
single dosages of 150 mcg/kg may be
safely repeated every three months, however higher dosing (800 mcg/kg) every three months was associated with
opthalmological complaints. (138)
Ivermectin Synergy with Artemisinin ?
Ivermectin and Artemesin have been safely used in combination
(ACT)
for treatment of malaria. Would Ivermectin combined with Artemisinin
serve as anti-cancer treatment ? The two agents use differing
mechanisms to accomplish the same thing, selectively increasing (ROS),
reactive oxygen species, inside the cancer cell. The Artemsinin works
via Fenton reaction, the oxidation reaction with iron, while the
Ivermectin acts on Chloride Ion channels. Would the two agents enhance
each others cell killing effects, working in synergy ? This would be an
excellent topic for future study with NIH funding.
Conclusion:
In my opinion, with the state of our knowledge of non-toxic targeted
agents, malignant cancer is now a curable disease, and suffering or
death from cancer should become a thing of the past. We have discussed
Artemisinin, the Chinese anti-malaria drug, which is also a targeted
non-toxic anti-cancer agent. The Artemisinin endoperoxide bridge reacts
with iron in the cancer cell to produce oxidative free radicals, which
induce apoptotic pathways. Down regulating the glutathione system with
sulfasalazine,
allicin (from garlic),
Feverfew (parthenolide) or
sulforaphane (from
Brocolli) renders the cancer cell more susceptible to oxidative damage
from Artemisinin and augments the cancer cell killing effects.
Combinations of these agents may prove useful, and should be funded for
future NIH research. We have discussed Ivermectin, an astonishingly safe
drug taken by 200 million people, with potent anti-cancer effects, at
micromolar concentrations, for both tumor bulk as well as cancer stem
cells.
The cancer patient of today may not have the luxury of time, and may
be inclined to proceed before prospective randomized studies are
completed. Indeed, prospective randomized trials may never be
forthcoming due to the nature of the drug discovery and approval system
in the US.
Even though Artemisinin and co-agents are considered relatively safe,
there may be toxicity at higher dosage, and the user must remain
vigilant, and reduce dosage should toxicity occur. It is recommended
that you work closely with a knowledgeable clinician.
Credit and Thanks goes to
Robert Jay Rowen, MD who brought Artemisin to my attention in a 2002 article in Townsend letter:
Artemisinin: From Malaria to Cancer Treatment .
Thanks to Stephen Levine, PhD, founder of Allergy Research Group for
introducing high quality Artemisinin products for the general public.
This article is part one, for part two
click here.
Financial Disclosure: I have none. I receive no
monetary inducements from, nor have any financial interests in any
manufacturer of artemisinin products.
Buy Allergy Research ARTEMISININ on Amazon
Buy Nutricology Artemisinin on Amazon.
Sources for Artemisinin and Derivatives
Artemisinin Products:
Hepalin.com
Artemix (Artesunate 50mg, Artemisinin 50mg, Artemether 40mg combo) contains 30 capsules in a bottle:$60
Link to :
Useful Artemisinin information page
Articles with related interest
Cancer as a Metabolic Disease
How do Cannabinoids Kill Cancer Cells
Artemisinin Support Group on Facebook
Jeffrey Dach MD
Links and References
video by Dr Henry Lai – May 2014
artemisinin- discovered by chinese in 1970’s used as anti-malaria
compound. Used for 30 years with safe profile. Leukemia cell will pick
up 1000 times more iron than a normal cell. Artemisinin is
approximately 100 times more potent in killing leukemia cells than
normal lymphocytes. Similar results for breast cancer cells.
Artemesisnin is very selective against cancer cells, Effective at low
dose. Few side effects. Oral capsule. Inexpensive. 1-2 mg/kg per day
effective in treating cancer, (in animals)
Discovery of Artemisinin video
The 2011 Lasker~DeBakey Clinical Medical Research Award honors a
scientist who discovered artemisinin and its utility for treating
malaria. Tu Youyou (China Academy of Chinese Medical Sciences, Beijing)
developed a therapy that has saved millions of lives across the globe,
especially in the developing world. An artemisinin-based drug
combination is now the standard regimen for malaria, and the World
Health Organization (WHO) lists artemisinin and related agents in its
catalog of “Essential Medicines.” Each year, several hundred million
people contract malaria. Without treatment, many more of them would die
than do now. Tu led a team that transformed an ancient Chinese healing
method into the most powerful antimalarial medicine currently available.
Nobel Prize in Medicine for Discovery of Artemisinin Video Published on Dec 8, 2015
Youyou Tu delivered her Nobel Lecture on 7 December 2015 at Aula
Medica, Karolinska Institutet in Stockholm. The lecture was presented in
Mandarin.
Youyou Tu: Discovery of Artemisinin – A gift from Traditional Chinese Medicine to the World
Artemisinin 2015 free
1) Das A K.
Anticancer effect of antimalarial artemisinin compounds. Ann Med Health Sci Res [serial online] 2015 [cited 2016 Feb 13];5:93-102.
Anticancer activity of artemisinin has been demonstrated primarily in vitro and in animal models. In a study, testing
55 cell lines showed that artesunate showed inhibitory effects against
leukemia, colon, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cells.
[39] The semisynthetic derivative DHA showed remarkable antineoplastic
activity against pancreatic, leukemic, osteosarcoma, and lung cancer
cells. [40] Moreover,
artemisone was superior to artemisinin and showed better synergism with other anti-cancer agents. [41]
Furthermore, artesunate proapoptotic effect is not affected in a doxorubicin-resistant leukemia cell line; rather it
potentiates doxorubicin’s apoptotic effects. [8]
how the antitumor activity is exerted following artemisinin activation is still not well-understood but is associated with
multiple
mechanisms, including reactive oxygen species (ROS), oxidative DNA
damage, sustained DNA double-strand breaks, and apoptosis. A
better understanding of common mechanisms under similar conditions in
different cell systems will greatly help developing targeted artemisinin
derivatives.
Experimental evidences, mostly animal studies indicate that
artemisinins and its derivatives may be a therapeutic alternative in the
future,
particularly in highly metastatic and aggressive cancers without developing drug resistance.
2011
2) Mercer, Amy E., et al. “
The
role of heme and the mitochondrion in the chemical and molecular
mechanisms of mammalian cell death induced by the artemisinin
antimalarials.” Journal of Biological Chemistry 286.2 (2011): 987-996.
2012
3) J Biomed Biotechnol. 2012; 2012: 247597.
Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug. Maria P. Crespo-Ortiz 1 ,* and Ming Q. Wei 2
Improvement of quality of life and survival of cancer patients will
be greatly enhanced by the development of highly effective drugs to
selectively kill malignant cells. Artemisinin and its analogs are
naturally occurring
antimalarials which have shown potent anticancer activity.
In primary cancer cultures and cell lines, their antitumor actions were
by inhibiting cancer proliferation, metastasis, and angiogenesis. In
xenograft models, exposure to artemisinins substantially reduces tumor
volume and progression. However, the rationale for the use of
artemisinins in anticancer therapy must be addressed by a greater
understanding of the underlying mechanisms involved in their cytotoxic
effects. The primary targets for artemisinin and the chemical base for
its preferential effects on heterologous tumor cells need yet to be
elucidated. The aim of this paper is to provide an overview of the
recent advances and new development of this class of drugs as potential
anticancer agents.
2015
4) Hongbao, Ma, Margaret Ma, and Yang Yan. “Cancer and Artemisinin
Research Literatures.” Cancer Biology, 2015;5(3), Brookdale Hospital,
Brooklyn, New York 11212, USA; 2 Cambridge, MA 02138, USA
Hongbao Cancer Artemisinin Research Cancer Biology 2015 . Nice listing of research articles
2015 Iron-dependent cell death –
Ferroptosis(53)
5) Ooko, E., et al. “
Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells.” Phytomedicine: international journal of phytotherapy and phytopharmacology 22.11 (2015): 1045.
The ferroptosis inhibitor ferrostatin-1 and the iron chelator
deferoxamine led to a significantly reduced cytotoxicity of artenimol,
indicating ferroptosis as cell death mode. Treatment with
ferroptosis-inducing agents such as artemisinin derivatives represents an attractive strategy for cancer therapy.
2014
Lysosomal Degradation of Ferritin
Cell mechanisms of artemisinin
6) Yang, Nai-Di, et al.
“Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin.” Journal of Biological Chemistry 289.48 (2014): 33425-33441. (full free)
Artesunate (ART) is an anti-malaria drug that has been shown to exhibit anti-tumor activity, and
functional lysosomes are reported to be required for ART-induced cancer cell death, whereas the underlying molecular mechanisms remain largely elusive. In this study, we aimed to elucidate the
molecular mechanisms underlying ART-induced cell death. We first confirmed that
ART induces apoptotic cell death in cancer cells.
Interestingly, we found that
ART preferably accumulates in the lysosomes and is able to
activate lysosomal function via promotion of lysosomal V-ATPase assembly.
Furthermore, we found that lysosomes function upstream of mitochondria
in reactive oxygen species production. Importantly, we provided evidence
showing that
lysosomal iron is required for the lysosomal activation and mitochondrial reactive oxygen species production induced by ART. Finally, we showed that
ART-induced
cell death is mediated by the release of iron in the lysosomes, which
results from the lysosomal degradation of ferritin, an iron storage
protein. Meanwhile, overexpression of ferritin heavy chain
significantly protected cells from ART-induced cell death. In addition,
knockdown of nuclear receptor coactivator 4, the adaptor protein for
ferritin degradation, was able to block ART-mediated ferritin
degradation and rescue the ART-induced cell death. In summary, our study
demonstrates that ART treatment activates lysosomal function and then
promotes ferritin degradation, subsequently
leading to the increase of lysosomal iron that is utilized by ART for its cytotoxic effect on cancer cells. Thus, our data reveal a new mechanistic action underlying ART-induced cell death in cancer cells.
Repression of NFkB – stimulates autophagy
7) Hu, Wei, et al. “
Dihydroartemisinin induces autophagy by suppressing NF-κB activation.” Cancer letters 343.2 (2014): 239-248.
Nuclear factor-kappa B (NF-κB) and autophagy are two
major regulators involved in both tumor initiation and progression.
However, the association between these two signaling pathways still
remains obscure. In this work, we demonstrate that
dihydroartemisinin
(DHA) stimulates the induction of autophagy in several cancer cell
lines through repression of NF-κB activity. We also show that
inhibiting NF-κB results in an accumulation of reactive oxygen species (ROS),
which participate in the stimulation of autophagy. These findings
present a pathway by which DHA promotes autophagy in cancer cells and
provide evidence for the DHA-induced sensitization effect of some
chemotherapeutics.
8) Toyokuni, Shinya. “
Iron and thiols as two major
players in carcinogenesis: friends or foes?.” The Changing Faces of
Glutathione, a Cellular Protagonist (2015): 114.
Toyokuni Shinya Iron thiols carcinogenesis Cellular Protagonist 2015
Leukemia 2012
9) Wang, Zeng, et al. “
Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity.” FEBS open bio 2 (2012): 103-112.
In summary, DHA induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity,
which includes the down-regulation of TfR expression and induction of apoptosis through the mitochondrial pathway.
Artemisinin synergistic with Resveratrol
10) Li, Peichun, et al. “
Synergic effects of artemisinin and resveratrol in cancer cells.” Journal of cancer research and clinical oncology 140.12 (2014): 2065-2075.
The aim of this study was to investigate whether resveratrol (Res)
combined with artemisinin (ART) possess synergistic effect on different
cancer cells.
MATERIALS AND METHODS:The viability of HepG2 and HeLa cells treated with
ART and Res was detected by 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium
bromide (MTT) assay. Combination index (CI) analysis and isobologram
were used to assess the synergistic effect of ART and Res in different
ratios. Wound-healing assay was used to investigate the migration rate.
AO staining and fluorescent microscopy measurements were performed to
detect the cell apoptosis. Reactive oxygen species (ROS) was measured
with 2’7′-dichlorofluorescein diacetate (DCFH-DA).
RESULTS:MTT assay indicated that ART and Res inhibited the growth of
HeLa and HepG2 cells in a dose-dependent manner. The combination of ART
and Res exhibited the strongest anticancer effect at the ratio of 1:2
(ART to Res). The combination of the two drugs also markedly reduced the
ability of cell migration. Apoptosis analysis showed that combination
of ART and Res significantly increased the apoptosis and necrosis rather
than use singly. Additionally, ROS levels were elevated by combining
ART with Res.
CONCLUSIONS:
Taken together, the present study suggested that ART
and Res possessed the synergistic anti-tumor effect. ART in combination
with Res could be an effective therapeutic strategy for cancer.
——————–
11) Berdelle, Nicole, et al. “
Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells.” Molecular cancer therapeutics 10.12 (2011): 2224-2233.
12) Chen, Kai, et al. “
Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells.” Anti-cancer drugs 25.6 (2014): 652-662.
We found that artesunate (ART) inhibited the growth of MCF-7 and MDA-MB-231 breast cancer cells.
ART
arrested the cell cycle in the G2/M phase, which was accompanied by an
upregulation of p21. ART upregulated the expression of Beclin1, an
initiator of autophagy (type II programmed cell death). In
addition, ART stimulated the aggregation of LC3, which is considered to
be a marker of autophagosome formation. We further verified the
transformation of LC3 from type I into type II. 3-MA, a classical
autophagy inhibitor, attenuated ART-induced autophagosome formation,
cell growth repression, G2/M arrest, and p21 upregulation. Autophagy
induction and p21 upregulation were also repressed by knockdown of
Beclin1. Furthermore, ART sensitized breast cancer cells to the
chemotherapeutic agent epirubicin through an autophagy-dependent
cascade. Our study showed that ART induced autophagy in breast cancer
cells and indicated that the anticancer effects of ART were exerted
through an autophagy pathway. Moreover, ART sensitized breast cancer
cells to epirubicin chemotherapy. Our results provide a basis for
further development of ART as a novel therapeutic agent for the
treatment of breast cancer.
Patents Dr Henry Lai
13)
Use of artemisinin and its derivatives in cancer therapy US 20100279976 A1
Abstract A method for treating cancer in a mammal includes
administering to the mammal in need thereof a therapeutically effective
amount of artemisinin (ART) or its derivative, such as
dihydroartemisinin (DHA), artemether (ARM), or artesunate (ARS) alone or
in combination with a chemotherapeutic agent, such as gemcitabine and
carboplatin.
A method for inhibiting tumor cell proliferation
includes contacting a tumor cell with ART or its derivative, such as
DHA, ARM, and ARS, in an amount effective to inhibit tumor cell
proliferation or in combination with a chemotherapeutic agent, such as
gemcitabine and carboplatin.
Dr Henry Lai
full pdf free
14)
http://www.ncbi.nlm.nih.gov/pubmed/22935909
Lai, Henry C., Narendra P. Singh, and Tomikazu Sasaki. “Development of
artemisinin compounds for cancer treatment.” Investigational new drugs
31.1 (2013): 230-246.
Artemisinin contains an endoperoxide moiety that can react with iron
to form cytotoxic free radicals. Cancer cells contain significantly more
intracellular free iron than normal cells and it has been shown that
artemisinin and its analogs selectively cause apoptosis in many cancer
cell lines. In addition, artemisinin compounds have been shown to have
anti-angiogenic, anti-inflammatory, anti-metastasis, and growth
inhibition effects. These properties make artemisinin compounds
attractive cancer chemotherapeutic drug candidates. However, simple
artemisinin analogs are less potent than traditional cancer
chemotherapeutic agents and have short plasma half-lives, and would
require high dosage and frequent administration to be effective for
cancer treatment. More potent and target-selective artemisinin-compounds
are being developed. These include artemisinin dimers and trimers,
artemisinin hybrid compounds, and tagging of artemisinin compounds to
molecules that are involved in the intracellular iron-delivery
mechanism. These compounds are promising potent anticancer compounds
that produce significantly less side effect than traditional
chemotherapeutic agents.
artemisone 2011
15) Cancer Chemother Pharmacol. 2011 Mar;67(3):569-77.
In vitro study of the anti-cancer effects of artemisone alone or in
combination with other chemotherapeutic agents. Gravett AM1, Liu WM,
Krishna S, Chan WC, Haynes RK, Wilson NL, Dalgleish AG.
anticancer effects of artemisone 2011 Gravett
Artemisinins are now established drugs for treatment of malaria.
These agents have been shown to possess impressive anti-cancer
properties. We have investigated the role of artemisone (ATM), a novel
derivative of artemisinin (ART) in a cancer setting both alone and in
combination with established chemotherapeutic agents.
METHODS:The anti-proliferative effects of ART and ATM were tested on a
panel of human cancer cells in vitro using the methylthiazoletetrazolium
assay, and the effect on cell cycling established by flow cytometry.
Immunoblot analyses were performed to determine effects at the molecular
level. Finally, ART and ATM were combined with the common anti-cancer
agents oxaliplatin, gemcitabine and thalidomide.
RESULTS:ART and ATM caused dose dependent decreases in cell number. ATM
was consistently superior to ART, with IC50 s significantly lower in the
former. Neither drug caused significant changes to the cell viability
(%viable cells >95%), but arrested cell cycling. Blockade was either
exclusively at the level of G1, or at all phases of the cell cycle, and
associated with reductions in cyclin D1, CDK4 and pRb. Combination
studies showed the anti-proliferative effect of ATM was often enhanced
by addition of the other drugs, whilst ART exhibited antagonistic
properties.
CONCLUSIONS:ART and ATM are active in cancer cell lines, with ATM
displaying the greater anti-proliferative effect when used alone. ATM
also enhances the effects of the above drugs, with ART being less likely
to improve activities. Taken together, ATM should be thought of as the
ART-derived compound next in line for further study.
16) Lai, Henry, et al. “Artemisinin-transferrin conjugate retards
growth of breast tumors in the rat.” Anticancer research 29.10 (2009):
3807-3810.
Lai Henry Artemisinin transferrin conjugate retards breast tumors 2009
————————
AML –
antimalarial agent mefloquine – Kills stem cells
17) Sukhai, Mahadeo A., et al. “
Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” The Journal of clinical investigation 123.1 (2013): 315-328.
To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the
antimalarial agent mefloquine as a compound that selectively kills AML cells and
AML stem cells in a panel of leukemia cell lines and in mice.
Would mefloquin act synergisticaly with artemisinin ?
————————-
transferrin receptors over-expressed in mantle cell lymphoma
18) Cancer Res. 2007 Feb 1;67(3):1145-54.
Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments. Lepelletier
Y1, Camara-Clayette V, Jin H, Hermant A, Coulon S, Dussiot M,
Arcos-Fajardo M, Baude C, Canionni D, Delarue R, Brousse N, Benaroch P,
Benhamou M, Ribrag V, Monteiro RC, Moura IC, Hermine O.
Herein, we show that
TfR is highly expressed on MCL cells,
The emergence of tumour-specific, molecularly targeted agents
signifies a paradigm shift in cancer therapy. Taken together with
immunohistochemistry data from MCL patients,
these results reveal the high level of TfR expression in MCL cells in vivo and in vitro.
Interestingly, the combined effect of A24 with VP-16 or with ara-C
was significantly more pronounced than that of any of these agents
alone. This difference was more markedly observed in EBV− cells ( Fig.
3B and C). Thus, A24 showed an inhibiting effect on MCL cell
proliferation that was both comparable with and synergistic with
conventional chemotherapeutic agents.
In spite of recent progress in MCL treatment, the disease prognosis
remains poor mainly due to the intrinsic resistance of malignant cells
to conventional chemotherapy ( 37– 39), and virtually, all patients,
even those who exhibit complete response, will relapse.
19)
http://leukemiaandlymphoma.eu/molecular-biology-mantle-cell-lymphoma-profiling-studies-new-therapeutic-strategies/fulltext
Obrador-Hevia, Antònia, et al. “Molecular biology of mantle cell
lymphoma: from profiling studies to new therapeutic strategies.” Blood
reviews 23.5 (2009): 205-216.
Transferrin receptor
Prevention of MCL establishment by routing the transferrin receptor
toward intracellular lysosomal compartments has been shown in an in
vitro model. 137 In fact this is an interesting approach that merits
further clinical studies for rapidly growing tumour cells such as some
MCL forms. Transferrin receptors are highly expressed in rapidly growing
tumours including MCL but not in their normal counterparts. These
tumours require transferrin for growth and survival. Therefore,
impairing the function of these iron uptake receptors promotes
apoptosis, and the activation of caspase 3 and 9 has been reported to
account for this effect. 137 A correlation between expression of
transferrin membrane receptor and Ki-67 has also been reported, 137
suggesting that this protein could represent an interesting target. The
implementation of this new therapeutic modality is favoured even further
by the fact that synergism with active cytotoxic drugs in MCL has been
found, such as ara-C (Aracytine) or VP-16 (Etoposide). 137 It has also
been reported that the transferrin receptor gene is up-regulated in MCL
relapses. 138 Accordingly, multiple therapeutic avenues can be
envisioned including the design of radioimmunoisotypes, or coupling of
monoclonal antibodies targeting this receptor with cytotoxic agents.
addition of iron renders artemsisin more cytotoxic
20) Free Radic Biol Med. 2004 Oct 1;37(7):998-1009.
ENHANCEMENT OF CYTOTOXICITY OF ARTEMISININS BY FERROUS IRON KAINA 2004
Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron.
Efferth T1, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Häfer R, Stamminger T, Oesch F, Kaina B, Marschall M.
Iron(II) heme-mediated activation of the peroxide bond of artemisinins
is thought to generate the radical oxygen species responsible for their
antimalarial activity. We analyzed the role of ferrous iron in the
cytotoxicity of artemisinins toward tumor cells.
Iron(II)-glycine sulfate (Ferrosanol)
and transferrin increased the cytotoxicity of free artesunate,
artesunate microencapsulated in maltosyl-beta-cyclodextrin, and
artemisinin toward
CCRF-CEM leukemia and U373 astrocytoma cells
1.5- to 10.3-fold compared with that of artemisinins applied without iron.
Growth inhibition by artesunate and ferrous iron correlated with
induction of apoptosis. Cell cycle perturbations by artesunate and
ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53
mutated WTK1 lymphoblastic cells showed that mutational status of the
tumor suppressor p53 did not influence sensitivity to artesunate. The
effect of ferrous iron and transferrin was reversed by monoclonal
antibody RVS10 against the transferrin receptor (TfR), which competes
with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed
TfR in 95 and 48% of the cell population, respectively, whereas TfR
expression in peripheral mononuclear blood cells of four healthy donors
was confined to 0.4-1.3%. This indicates that artemisinins plus ferrous
iron may affect tumor cells more than normal cells.
iron in cancer cells
21) Kwok, Juliana C., and Des R. Richardson. “
The iron metabolism of neoplastic cells: alterations that facilitate proliferation?.” Critical Reviews in Oncology/Hematology 42.1 (2002): 65-78.
For many years it has been known that
neoplastic cells
express high levels of the transferrin receptor 1 (TfR1) and internalize
iron (Fe) from transferrin (Tf) at a tremendous rate.
Considering the high requirement of neoplastic cells for Fe,
understanding its metabolism is vital in terms of devising potential new
therapies. Apart from TfR1, a number of molecules have been identified
that may have roles in Fe metabolism and cellular proliferation. These
molecules include transferrin (Tf), the oestrogen-inducible transferrin
receptor-like protein, transferrin receptor 2 (TfR2), melanotransferrin
(MTf), ceruloplasmin, and ferritin. In the present review these latter
molecules are discussed in terms of their potential functions in tumour
cell Fe metabolism and proliferation. Further studies are essential to
determine the specific roles of these proteins in the pathogenesis of
cancer.
Cancer cells generally have higher numbers of the TfR1 than their normal counterparts [[3], [4], [5]]
and take up Fe at a higher rate [[6], [7], [8]]. This is reflected by the
ability of tumours to be radiolocalized using 67Ga [9], that binds to the Tf Fe-binding site and is delivered via its binding to the TfR1 [[4], [10]].
22) Kundu, Chanakya Nath, et al. “Anti-malarials are anti-cancers
and vice versa–One arrow two sparrows.” Acta tropica 149 (2015):
113-127.
Antimalarials are anticancers Kundu Acta tropica 2015
Transferrin Factor Synthesized in Testicles, kidney, spleen
23) J Biol Chem. 1980 Oct 25;255(20):9523-5.
Sertoli cells synthesize and secrete transferrin-like protein.Skinner MK, Griswold MD. Sertoli cells of the testes synthesize Tf to provide proliferating spermatocytes with Fe [71]. kidney, spleen also.
Curcumin anti-cancer Effects
24) Hasanali, Zainul, Kamal Sharma, and Elliot Epner. “
Flipping the cyclin D1 switch in mantle cell lymphoma.” Best Practice & Research Clinical Haematology 25.2 (2012): 143-152.
Curcumin, a plant flavonoid that is available naturally in turmeric and as an herbal supplement, has been shown in vitro to
downregulate cyclins D1
and D3 at both the transcriptional and post-transcriptional levels in
MCL and MM cell lines [50] . Curcumin is known to inhibit the COP9
signalosome, a multiprotein complex similar to the proteasome [51],
[52], and [53]. Our laboratory has demonstrated that
curcumin and bortezomib synergize in downregulating
protein levels of cyclins D1 and D3 in MM and MCL cells [35] . Clinical
trials of this agent in combination in lymphoid malignancies alone or
in combination with bortezomib are ongoing.
Curcumin against Four MCL cell lines
25) Shishodia, Shishir, et al. “
Curcumin
(diferuloylmethane) inhibits constitutive NF-κB activation, induces
G1/S arrest, suppresses proliferation, and induces apoptosis in mantle
cell lymphoma.” Biochemical pharmacology 70.5 (2005): 700-713. Biochem Pharmacol. 2005 Sep 1;70(5):700-13.
Shishodia S1, Amin HM, Lai R, Aggarwal BB.
Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin’s lymphoma, is characterized by the
overexpression of cyclin D1
which plays an essential role in the survival and proliferation of MCL.
Because of MCL’s resistance to current chemotherapy, novel approaches
are needed. Since MCL cells are known to
overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a
variety of MCL cell lines.
All four MCL cell lines examined had overexpression of cyclin D1,
constitutive active NF-kappaB and IkappaB kinase and phosphorylated
forms of IkappaBalpha and p65. This correlated with expression of TNF,
IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB.
On treatment of cells with curcumin, however,
downregulated constitutive active NF-kappaB
and inhibited the consitutively active IkappaBalpha kinase (IKK), and
phosphorylation of IkappaBalpha and p65. Curcumin also inhibited
constitutive activation of Akt, needed for IKK activation.
Consequently,
the expression of all NF-kappaB-regulated gene products, were
downregulated by the polyphenol leading to the suppression of
proliferation, cell cycle arrest at the G1/S phase of the cell cycle and
induction of apoptosis as indicated by caspase activation, PARP
cleavage, and annexin V staining. That NF-kappaB activation is
directly linked to the proliferation of cells, is also indicated by the
observation that peptide derived from the IKK/NEMO-binding domain and
p65 suppressed the constitutive active NF-kappaB complex and inhibited
the proliferation of MCL cells. Constitutive
NF-kappaB activation was found to be due to TNF,
as anti-TNF antibodies inhibited both NF-kappaB activation and
proliferation of cells. Overall, our results indicate that curcumin
inhibits the constitutive NF-kappaB and IKK leading to suppression of
expression of NF-kappaB-regulated gene products that results in the
suppression of proliferation, cell cycle arrest, and induction of
apoptosis in MCL.
26) Choudhuri, Tathagata, et al. “
Curcumin
selectively induces apoptosis in deregulated cyclin D1-expressed cells
at G2 phase of cell cycle in a p53-dependent manner.” Journal of Biological Chemistry 280.20 (2005): 20059-20068.
All
of these data suggest that curcumin can exert its apoptogenic effect in
those cells whose cyclin D1 expression is deregulated due to genetic
manipulations.
27) Singh, Amareshwar TK, et al. “
Curcumin nanodisk-induced apoptosis in mantle cell lymphoma.” Leukemia & lymphoma 52.8 (2011): 1537-1543.
28) Tadmor, Tamar, and Aaron Polliack. “
Mantle cell lymphoma: curcumin nanodisks and possible new concepts on drug delivery for an incurable lymphoma.” Leukemia & lymphoma 52.8 (2011): 1418.
29) Yallapu, Murali M., Meena Jaggi, and Subhash C. Chauhan. “
Curcumin nanomedicine: a road to cancer therapeutics.” Current pharmaceutical design 19.11 (2013): 1994.
—————————————————
Cannabinoid Extracts Anti-Cancer Effects
30) Semin Cancer Biol.
2011 Nov;21(5):313-21.
The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas. Wasik AM1, Christensson B, Sander B.
The initiating oncogenic event in mantle cell lymphoma (MCL) is the
translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic
aberrations are necessary for an overt lymphoma to arise. Like other B
cell lymphomas, MCL at some points during the oncogenesis is dependent
on interactions with other cells and factors in the microenvironment.
The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and
CB2) are expressed at low levels on non-malignant lymphocytes and at
higher levels in MCL and other lymphoma subtypes. In this review we give
an overview of what is known on the role of the cannabinoid receptors
and their ligands in lymphoma as compared to non-malignant T and B
lymphocytes. In MCL cannabinoids mainly reduce cell proliferation and
induce cell death. Importantly, our recent findings demonstrate that
cannabinoids may induce either apoptosis or another type of programmed
cell death, cytoplasmic vacuolation/paraptosis in MCL. The signalling to
death has been partly characterized. Even though cannabinoid receptors
seem to be expressed in many other types of B cell lymphoma, the
functional role of cannabinoid receptor targeting is yet largely
unknown. In non-malignant B and T lymphocytes, cannabinoid receptors are
up-regulated in response to antigen receptor signalling or CD40. For T
lymphocytes IL-4 has also a crucial role in transcriptional regulation
of CB1. In lymphocytes, cannabinoid act in several ways – by affecting
cell migration, cytokine response, at high doses inhibit cell
proliferation and inducing cell death. The possible role for the
endocannabinoid system in the immune microenvironment of lymphoma is
discussed.
31)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278325/
Wasik AM, Nygren L, Almestrand S, et al. Perturbations of the
endocannabinoid system in mantle cell lymphoma: correlations to clinical
and pathological features. Oncoscience.
2014;1(8):550-557.
32)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171598/
Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in
cancer: current status and future implications. Oncotarget.
2014;5(15):5852-5872.
>>>>>>>>>>>>>>>>>>>>>>>>>
NICE IMAGE OF GREEN STAIN FOR CB1 RECEPTOR
33)
http://www.nature.com/leu/journal/v17/n9/full/2403057a.html
Leukemia (
2003) 17, 1880–1890. doi:10.1038/sj.leu.2403057
High level of cannabinoid receptor 1, absence of regulator of G protein
signalling 13 and differential expression of Cyclin D1 in mantle cell
lymphoma
T C Islam1, A C Asplund1, J M Lindvall1, L Nygren2, J Liden3, E Kimby4, B Christensson2, C I E Smith1 and B Sander2
34) full pdf
https://www.researchgate.net/profile/Eva_Kimby2/publication/7432907_Cannabinoid_receptor_ligands_mediate_growth_inhibition_and_cell_death_in_mantle_cell_lymphoma/links/02e7e52bae47431e6b000000.pdf
http://febsletters.org.marlin-prod.literatumonline.com/article/S0014-5793(05)01380-3/abstract
Flygare, Jenny, et al. “Cannabinoid receptor ligands mediate growth
inhibition and cell death in mantle cell lymphoma.” FEBS letters 579.30 (
2005): 6885-6889.
We have earlier reported
overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL),
a B cell non-Hodgkin lymphoma. In this study, treatment with
cannabinoid receptor ligands caused a decrease in viability of MCL
cells, while control cells lacking CB1 were not affected. Interestingly,
equipotent doses of the CB1 antagonist SR141716A and the CB1/CB2
agonist anandamide inflicted additive negative effects on viability.
Moreover, treatment with the CB1/CB2 agonist Win-55,212-2 caused a
decrease in long-term growth of MCL cells in culture.
Induction of apoptosis, as measured by FACS/Annexin V–FITC, contributed to the growth suppressive effect of Win-55,212-2.
Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.
35)
http://molpharm.aspetjournals.org/content/70/5/1612.long
Gustafsson, Kristin, et al. “Cannabinoid receptor-mediated apoptosis
induced by R (+)-methanandamide and Win55, 212-2 is associated with
ceramide accumulation and p38 activation in mantle cell lymphoma.” Molecular pharmacology 70.5 (
2006): 1612-1620.
36) Int J Cancer.
2008 Sep 1;123(5):1025-33.
Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.
Gustafsson K1, Wang X, Severa D, Eriksson M, Kimby E, Merup M, Christensson B, Flygare J, Sander B.
Endogenous and synthetic cannabinoids exert antiproliferative and
proapoptotic effects in various types of cancer and in mantle cell
lymphoma (MCL). In this study, we evaluated the expression of
cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin
lymphomas of B cell type (n = 62). A majority of the lymphomas expressed
higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid
tissue.
With the exception of MCL, which uniformly overexpresses both CB1 and CB2,
the levels of cannabinoid receptors within other lymphoma entities were
highly variable, ranging from 0.1 to 224 times the expression in
reactive lymph nodes. Low levels of the splice variant CB1a, previously
shown to have a different affinity for cannabinoids than CB1, were
detected in 44% of the lymphomas, while CB1b expression was not
detected. In functional studies using MCL, Burkitt lymphoma (BL),
chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines,
the stable anandamide analog R(+)-methanandamide (R(+)-MA)
induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors,
but not in BL. In vivo treatment with R(+)-MA caused a significant
reduction of tumor size and mitotic index in mice xenografted with human
MCL. Together, our results suggest that therapies
using
cannabinoid receptor ligands will have efficiency in reducing tumor
burden in malignant lymphoma overexpressing CB1 and CB2.
37) Gustafsson, Kristin, et al. “
Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism.” Molecular Cancer Research 7.7 (
2009): 1086-1098.
Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids.
Here, we investigated the pathways of ceramide accumulation in the MCL
cell line Rec-1 using the stable endocannabinoid analogue
R(+)-methanandamide (R-MA). We further interfered with the conversion of
ceramide into sphingolipids that promote cell growth. Treatment with
R-MA led to increased levels of ceramide species C16, C18, C24, and
C24:1 and transcriptional induction of ceramide synthases (CerS) 3 and
6. The effects were attenuated using SR141716A, which has high affinity
to cannabinoid receptor 1 (CB1). The CB1-mediated induction of CerS3 and
CerS6 mRNA was confirmed using Win-55,212-2. Simultaneous silencing of
CerS3 and CerS6 using small interfering RNA abrogated the R-MA-induced
accumulation of C16 and C24. Inhibition of either of the enzymes serine
palmitoyl transferase, CerS, and dihydroceramide desaturase within the
de novo ceramide pathway reversed ceramide accumulation and cell death
induced by R-MA treatment. To enhance the cytotoxic effect R-MA,
sphingosine kinase-1 and glucosylceramide synthase, enzymes that convert
ceramide to the pro-proliferative sphingolipids sphingosine-1-phospate
and glucosylceramide, respectively, were inhibited. Suppression of
either enzyme using inhibitors or small interfering RNA potentiated the
decreased viability, induction of cell death, and ceramide accumulation
induced by R-MA treatment. Our findings suggest that
R-MA induces cell death in MCL via CB1-mediated up-regulation of the de novo ceramide synthesis pathway.
Furthermore, this is the first study were the cytotoxic effect of a
cannabinoid is enhanced by modulation of ceramide metabolism. (Mol
Cancer Res 2009;7(7):1086–98)
38) Wasik, A. M., et al. “
WIN55, 212-2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells.” Cell death & disease 2.11 (2011): e225.
Cannabinoid receptors 1 (CB1) and/or 2 (CB2) are overexpressed in many
types of human malignancies including mantle cell lymphoma (MCL).
Agonists to CB1 and CB2 promote ceramide de novo synthesis,
p38–mitogen-activated protein kinase-dependent activation of caspase-3
and apoptotic cell death in most MCLs. However, in this report we
describe that in some MCLs the response to treatment with cannabinoids
decreased cell viability as assessed by metabolic activity but did not
involve the caspase-3 cascade or loss of plasma membrane integrity. Both
primary cells from one MCL patient and the MCL cell line Granta519
responded to treatment with cannabinoids by formation of
cycloheximide-sensitive cytoplasmic vacuoles, but did not enter
apoptosis. The persistent expression of mammalian homolog of Atg8 with
microtubule-associated protein-1 light chain-3 II (LC3 II) and p62, as
well as the lack of protection from chloroquine, indicates that
lysosomal degradation is not involved in this cytoplasmic vacuolation
process, distinguishing from classical autophagy. Transmission electron
microscopy images and immunofluorescence staining of endoplasmic
reticulum (ER) chaperone calreticulin showed that the vacuoles were of
ER origin and that chromatin remained normal. These features resemble
paraptosis-like cell death—a third type of a programmed cell death not
previously described in response to cannabinoids.
Sulfazalazine
39) Ishimoto, Takatsugu, et al. “CD44 variant regulates redox status
in cancer cells by stabilizing the xCT subunit of system xc− and thereby
promotes tumor growth.” Cancer cell 19.3 (2011): 387-400.
CD44 regulates redox status in cancer cells by stabilizing xCT Cancer cell 2011 Ishimoto Takatsugu The xCT Inhibitor
Sulfasalazine Suppresses CD44-Dependent Tumor Growth and Promotes Activation of p38MAPK in Tumor Cells In Vivo – Stem Cells !!!
40) Lewerenz, Jan, et al. “The cystine/glutamate antiporter system
xc− in health and disease: from molecular mechanisms to novel
therapeutic opportunities.” Antioxidants & redox signaling 18.5
(2013): 522-555.
The cystine glutamate antiporter system xc in health and disease Lewerenz Jan 2013
Early evidence suggested that nonsteroidal anti-inflammatory drugs also
inhibit system xc – (15). On this basis, the Gout lab identified the
FDA-approved drug
sulfasalazine, commonly used to treat
chronic inflammatory diseases such as rheumatoid arthritis, as a potent
system xc – inhibitor (79). However, this compound is also a
potent inhibitor of nuclear factor kappa B (NF-jB) activation (283).
41) Gout, P. W., et al. “
Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x c-cystine transporter: a new action for an old drug.” Leukemia (08876924) 15.10 (2001). 1Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada
42) Doxsee, Daniel W., et al. “
Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy.” The Prostate 67.2 (2007): 162-171.
43) Chung, W. Joon, and Harald Sontheimer. “
Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor‐κB.” Journal of neurochemistry 110.1 (2009): 182-193.
44) Guan, Jun, et al. “
The x c− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine.” Cancer chemotherapy and pharmacology 64.3 (2009): 463-472.
45) Dixon, Scott J., et al. “Pharmacological inhibition of
cystine–glutamate exchange induces endoplasmic reticulum stress and
ferroptosis.” Elife 3 (2014): e02523.
Pharmacological
inhibition of cystine glutamate exchange induces endoplasmic reticulum
stress and ferroptosis.Elife 2014 Dixon SCott
46) Narang, Vishal S., et al. “Sulfasalazine-induced reduction of
glutathione levels in breast cancer cells: enhancement of
growth-inhibitory activity of doxorubicin.” Chemotherapy 53.3 (2007):
210-217.
Sulfasalazine induced reduction of glutathione levels in breast cancer cells Narang 2007 Chemotherapy
Background: We previously showed that the anti-inflammatory drug, sulfasalazine (salicylazosulfapyridine, SASP),
can arrest proliferation of MCF-7 and MDA-MB-231 mammary cancer cells
by inhibiting uptake of cystine via the xc– cystine/glutamate
antiporter. Here we examined SASP with regard to reduction of cellular
glutathione (GSH) levels and drug efficacy-enhancing ability. Methods:
GSH levels were measured spectrophotometrically. Cellular drug retention
was determined with 3H-labeled methotrexate, and drug efficacy with a
colony formation assay. Results: Incubation of the mammary cancer cells
with SASP (0.3–0.5 mM) led to reduction of their GSH content in a time-
and concentration-dependent manner. Similar to MK-571, a multidrug
resistance-associated protein inhibitor, SASP increased intracellular
accumulation of methotrexate. Preincubation of cells with SASP (0.3 mM)
significantly enhanced the potency of the anticancer agent doxorubicin
(2.5 nM). Conclusions: SASP-induced reduction of cellular GSH levels can
lead to growth arrest of mammary cancer cells and enhancement of
anticancer drug efficacy.
We also showed, for the first time, that sulfasalazine
(salicylazosulfapyridine, SASP), an anti-inflammatory drug used against
inflammatory bowel disease
and rheumatoid arthritis, is a potent inhibitor of x c – – mediated
cystine uptake [16] , and that it can markedly inhibit proliferation of
human breast carcinoma cells at relatively low concentrations (0.2–0.5 m
M ) via cystine starvation [17] .
The human breast carcinoma cell lines, MCF-7 (estrogen receptor
positive) and MDA-MB-231 (estrogen receptor negative, highly invasive),
From Rheumatoid artritis.net:
How is sulfasalazine taken?
Sulfasalazine comes in a 500-mg tablet for oral administration and it typically started at a dose of
500 mg per day
and increased by 500 mg every week, while monitoring for side effects,
until a daily target dose (this is determined by your weight,
approximately 40 mg/kg) is reached. For most adult patients with RA, the
final daily dose ranges from
2000-3000 mg (2-3 grams).
If gastrointestinal (GI) side effects are problematic, divided doses
can be used or a special enteric-coated form (Azulfidine EN-tabs) to
protect against GI effects. To help prevent stomach upset, you should
take sulfasalazine with food, followed by a full glass of water.1,2
——————————————————————————————
Chloroquin synergistic with Artemisinin ?
47) Ganguli, Arnab, et al. “Inhibition of autophagy by chloroquine
potentiates synergistically anti-cancer property of artemisinin by
promoting ROS dependent apoptosis.” Biochimie 107 (2014): 338-349.
Inhibition
of autophagy by chloroquine potentiates synergistically anti-cancer
property of artemisinin by promoting ROS dependent apoptosis Ganguli
Biochimie 2014
The appropriate manipulation of autophagy by using CQ provides a
powerful strategy to increase the Potency of selective anticancer
property of ART.
However, the low toxicity and low bio-availability make it unsuitable
for use as an anticancer agent. Works are going on to try to increase
the potency of artemisinin and make it acceptable as an anticancer drug.
One of the well known late phase autophagy inhibitor is chloroquine
(CQ). For more than six decades CQ has been using to treat several
diseases (like, malaria, rheumatoid arthritis, lupus) because of its
high effectiveness and well tolerated by human [23]
Chloroquin, its protonated forms are trapped within the acidic
vacuoles (late endosome and lysosome), causing increased in pH, inactive
lysosomal hydrolysates, thus increase the autolysosomes accumulation by
inhibiting
the autophagy.
For
pretreatment regime, we treated A549 cells (lung
cancer) with 25-100 μM CQ for 12 h and subsequently after washing the
cells, treatment with 75 μM ART for 72 h was performed.
For co-treatment, we used 75 μM ART and different concentration of CQ
(2.5-25 μM) simultaneously to treat A549 cells for 72 h. In both the
cases, we measured cell viability by MTT assay and calculated
combination index (CI) (Fig 5A-D). We found that CI value of
pre-treatment (Fig. 5A and C) were much more lower than CI values of
co-treatment (Fig.5 B and D), indicating pre-treatment had synergistic
effect where as co-treatment had nearly an additive effect.
Furthermore co-treatment also reduced cell viability of normal cells
(Fig. 5E) but pretreatment did not have any cytotoxic effect towards
normal cells (Fig. 5F).
In control experiments, when cells were treated with separately CQ (50
μM for 12 h) and ART (75 μM for 72 h), and the apoptotic populations
were 3% and 16% respectively, but in case of combination treatment,
apoptotic population was increased to 40% (Fig. 6C).
We observed that NAC significantly reduced AVOs in both single and
double treated A549 cells (Fig. 8C). Furthermore, scavenging ROS by NAC
decreased the cleaved caspase 3 expression (Fig. 8E) and subsequently
blocked apoptotic cells death (Fig. 8D)
pretreatment of CQ was found to be more effective to increase the potency of artemisinin than co-treatment (Fig.5A-E).
48) Solomon, V. Raja, and Hoyun Lee. “Chloroquine and its analogs: a
new promise of an old drug for effective and safe cancer therapies.”
European journal of pharmacology 625.1 (2009): 220-233.
Chloroquine
and its analogs a new promise of an old drug for effective and safe
cancer therapies Solomon Raja Hoyun Lee European journal of pharmacology
2009
49) Kimura, Tomonori, et al. “
Chloroquine in cancer therapy: a double-edged sword of autophagy.” Cancer research 73.1 (2013): 3-7.
The dosage of chloroquine usually ranges between 100 and 500 mg/day.
Side effects are minimal at low doses, while many more toxic effects
occur at higher doses, such as visual disturbances, gastrointestinal
upset, electrocardiographic changes, headache, and pruritus.
50) Eur J Pharmacol. 2016 Jan 15;771:139-44.
Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies. Pascolo S1.
Chloroquine, a drug used for
over 80 years to treat and
prevent malaria and, more recently, to treat autoimmune diseases, is
very safe but has a plethora of dose-dependent effects.
By increasing pH in acidic compartments it inhibits for example lysosomal enzymes.
In the context of cancer, Chloroquine was found to have direct effects
on different types of malignancies that could potentiate chemotherapies.
For example, the anti-malaria drug may inhibit both the
multidrug-resistance pump and autophagy (mechanisms that tumor cells may
use to resist chemotherapies), intercalate in DNA and enhance the
penetration of chemotherapeutic drugs in cells or solid cancer tissues.
However, these activities were mostly demonstrated at high doses of
Chloroquine (higher than 10mg/kg or 10mg/l i.e. ca. 31μM). Nevertheless,
it was reported that daily uptake of clinically acceptable doses (less
than 10mg/kg) of Chloroquine in addition to chemo-radio-therapy
increases the survival of glioblastoma patients (Sotelo et al., 2006;
Briceno et al., 2007). However,
the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined.
The present article reviews the several known direct and indirect
effects of different doses of Chloroquine on cancer and how those
effects may indicate that a fine tuning of the dose/schedule of
Chloroquine administration versus chemotherapy may be critical to obtain
an adjuvant effect of Chloroquine in anti-cancer treatments. We
anticipate that the appropriate (time and dose) addition of Chloroquine
to the standard of care may greatly and safely potentiate current
anti-cancer treatments.
51) Sukhai, Mahadeo A., et al. “
Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.” Journal of Clinical Investigation 123.1 (2013): 315.
mefloquin and artemisinin combination
However, strikingly, 10 of these, including the artemisinin class of
antimalarials (27, 28), proved to be compounds that are known to
increase the production of ROS.
Synergistic combinations of mefloquine and artenimol or artesunate also synergistically increased ROS production
mefloquine specifically targets lysosomal function. This finding is
consistent with mefloquine’s known ability to preferentially accumulate
in lysosomes of the malarial parasite
Mefloquine directly disrupted lysosomes isolated from AML cell lines
and primary AML patients’ samples, in a dose-dependent manner, as
measured by release of cathepsins B and L
The effects of mefloquine were specific to lysosomes, as mefloquine treatment did not disrupt isolated mitochondria
In a dose-dependent manner, mefloquine disrupted lysosomes in TEX
leukemia cells and mefloquine-sensitive cells from AML patients, but not
normal hematopoietic cells
Taken together, these data point to mefloquine-mediated lysosomal
disruption as the cellular mechanism underlying antileukemic action.
AML cells have increased lysosomal mass compared with normal hematopoietic cells.
TEM revealed that lysosomes are
larger in primary human AML cells,
including the CD34+ AML cells, as well as in AML cell lines, in
comparison to the lysosomes found in normal human CD34+ hematopoietic
cells
Here we report that mefloquine, a quinoline approved for the treatment and prevention of malaria (23, 24),
has
toxicity for human AML cells including AML progenitors, while sparing
normal human hematopoietic cells treated with the same doses.
serum concentrations of mefloquine up to 5 μM have been reported
in individuals receiving 250 mg weekly for malaria prophylaxis (59,
60). Thus, antileukemia concentrations of mefloquine may be
pharmacologically achievable.
The antimalarial chloroquine is structurally similar to mefloquine
and inhibits the degradation of autophagy targets in the
autophagolysosome. Through this mechanism,
chloroquine can induce cell death and sensitize cells to chemotherapy
(including imatinib mesylate in chronic myeloid leukemia; refs. 63–66)
and radiation. However, as it involves induction of lysosome disruption,
the mechanism of action of mefloquine appears distinct from that of
chloroquine and other inhibitors of autophagy.
52) Neuro Oncol. 2010 May;12(5):473-81.
Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent.
Geng Y1, Kohli L, Klocke BJ, Roth KA.
Glioblastoma (GBM) is a high-grade central nervous system malignancy
and despite aggressive treatment strategies, GBM patients have a median
survival time of just 1 year.
Chloroquine (CQ), an
antimalarial lysosomotropic agent, has been identified as a potential
adjuvant in the treatment regimen of GBMs. However, the mechanism of
CQ-induced tumor cell death is poorly defined. We and others have shown
that CQ-mediated cell death may be p53-dependent and at least in part
due to the intrinsic apoptotic death pathway. Here, we investigated the
effects of CQ on 5 established human GBM lines, differing in their p53
gene status. CQ was found to induce a concentration-dependent death in
each of these cell lines. Although CQ treatment increased caspase-3-like
enzymatic activity in all 5 cell lines, a broad-spectrum caspase
inhibitor did not significantly attenuate death. Moreover,
CQ
caused an accumulation of autophagic vacuoles in all cell lines and was
found to affect the levels and subcellular distribution of cathepsin D,
suggesting that altered lysosomal function may also play a role in
CQ-induced cell death. Thus,
CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis.
To potentially identify more potent chemotherapeutics, various CQ
derivatives and lysosomotropic compounds were tested on the GBM cells.
Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and
given their superior blood-brain barrier penetration compared with CQ
may prove more efficacious as chemotherapeutic agents for GBM patients.
What is the usual dose of Chloroquine? From rheuminfo.com
Chloroquine is available in 250 mg tablets. The dose is based on your
lean body weight with the standard dose ranging from one-half (125 mg)
to one tablet (250 mg) per day. The dose should be no more than 3
mg/kg/day of lean body weight.
Why do I need to see an Ophthalmologist (Eye Doctor) when I am taking Chloroquine?
As mentioned above, Chloroquine can cause damage to the back of the
eye (retina). Early eye toxicity is not usually a serious problem.
However, once serious damage occurs, it is permanent. Therefore,
appropriate monitoring of the eye by a medical specialist familiar with
the side-effects of Chloroquine is essential. The eye examination
includes regular tests such as vision and eye pressure. It also includes
tests which are not part of a regular eye check-up such as testing for
colour vision and testing your visual fields. Your doctor will usually
ask you to see an ophthalmologist every 6-24 months.
Ferroptostis
53) Xie, Y., et al. “
Ferroptosis: process and function.” Cell Death & Differentiation (2016).
56) Nandakumar, Dalavaikodihalli Nanjaiah, et al. “
Curcumin-artemisinin combination therapy for malaria.” Antimicrobial agents and chemotherapy 50.5 (2006): 1859-1860.
Synergy with allicin full pdf
57) .
Synergistic Anticancer Effect of Artesunate with Allicin in Osteosarcoma Jiang_2013 Asian Pac J Cancer Prev. 2013;14(8):4615-9
The synergistic anticancer effect of
artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Jiang W1, Huang Y, Wang JP, Yu XY, Zhang LY.
Artesunate, extracted from Artemisia annua, has been proven to have
anti-cancer potential. Allicin, diallyl thiosulfinate, the main
biologically active compound derived from garlic, is also of interest in
cancer treatment research. This object of this report was to document
synergistic effects of artesunate combined with allicin on osteosarcoma
cell lines in vitro and in vivo.
METHODS:After treatment with artesunate and allicin at various
concentrations, the viability of osteosarcoma cells was analyzed by MTT
method, with assessment of invasion and motility, colony formation and
apoptosis. Western Blotting was performed to determine the expression of
caspase-3/9, and activity was also detected after drug treatment.
Moreover, in a nude mouse model established with orthotopic xenograft
tumors, tumor weight and volume were monitored after drug administration
via the intraperitoneal (i.p.) route.
RESULTS:The viability of osteosarcoma cells in the combination group was
significantly decreased in a concentration and time dependent manner;
moreover, invasion, motility and colony formation ability were
significantly suppressed and the apoptotic rate was significantly
increased through caspase-3/9 expression and activity enhancement in the
combination group. Furthermore, suppression of tumor growth was evident
in vivo.
CONCLUSION:Our results indicated that artesunate and allicin in
combination exert synergistic effects on osteosarcoma cell proliferation
and apoptosis.
synergy with resveratrol
58) J Cancer Res Clin Oncol. 2014 Dec;140(12):2065-75.
Synergic effects of artemisinin and resveratrol in cancer cells.
Li P1, Yang S, Dou M, Chen Y, Zhang J, Zhao X.
The aim of this study was to investigate whether resveratrol (Res)
combined with artemisinin (ART) possess synergistic effect on different
cancer cells.
MATERIALS AND METHODS:The viability of HepG2 and HeLa cells treated with
ART and Res was detected by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. Combination index (CI) analysis and isobologram were used to
assess the synergistic effect of ART and Res in different ratios.
Wound-healing assay was used to investigate the migration rate. AO
staining and fluorescent microscopy measurements were performed to
detect the cell apoptosis. Reactive oxygen species (ROS) was measured
with 2’7′-dichlorofluorescein diacetate (DCFH-DA).
RESULTS:MTT assay indicated that ART and Res inhibited the growth of
HeLa and HepG2 cells in a dose-dependent manner. The combination of ART
and Res exhibited the strongest anticancer effect at the ratio of 1:2
(ART to Res). The combination of the two drugs also markedly reduced the
ability of cell migration. Apoptosis analysis showed that combination
of ART and Res significantly increased the apoptosis and necrosis rather
than use singly. Additionally, ROS levels were elevated by combining
ART with Res.
CONCLUSIONS:Taken together, the present study suggested that
ART and Res possessed the synergistic anti-tumor effect. ART in combination with Res could be an effective therapeutic strategy for cancer.
59) Tolomeo,M. et al. (2005) Pterostilbene and 3-hydroxypterostilbene
are effective apoptosis-inducingagents in MDR and BCR-ABL-expressing
leukemia cells. Int. J. Biochem. Cell Biol. 37, 1709–1726
Pterostilbene apoptosis in MDR leukemia cells Tolomeo 2005
Gleditsia sinensis
60) Oncol Rep. 2003 Sep-Oct;10(5):1601-7.
Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia. Chow LM1, Chui CH, Tang JC, Teo IT, Lau FY, Cheng GY, Wong RS, Leung TW, Lai KB, Yau MY, Gou D, Chan AS.
The anti-leukemia activity of the saponin rich Gleditsia sinensis Lam.
fruit extract (GSE) was investigated on cancer cell lines and bone
marrow cells obtained from consented patients with chronic myelogenous
leukemia (CML) and acute myelogenous leukemia (AML) during presentation.
The growth inhibitory activity of the extract was determined by
[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]
(MTS) assay. Colony formation assay was performed to investigate the
regeneration potential. Cellular morphology change was studied.
Apoptosis was demonstrated by DNA electrophoresis, reverse transcription
polymerase chain reaction (RT-PCR) and flow cytometry. The mean
concentration to inhibit the cell growth by 50% (MTS50) was 18+/-1.6
micro g/ml for K562 CML cell line and 12+/-1.3 micro g/ml for HL-60
acute promyelocytic leukemia cell line. Patient samples showed a mean
MTS50 of 13-28 micro g/ml. Non-malignant hematological disorder bone
marrow samples showed a mean MTS50 from 45 to 53 micro g/ml. Loss of
regeneration property after treatment with GSE of these two cancer cell
lines were confirmed by colony formation assay. GSE was able to induce
cell shrinkage in K-562. DNA laddering was observed by incubating the
leukemia cells with GSE. RT-PCR demonstrated that the pro-apoptic gene
bax was induced while the anti-apoptic gene bcl-2 and cell cycle active
gene PCNA were reduced. Flow cytometric analysis showed that the
apoptotic effect of GSE on leukemia cell line was time- and
dose-dependent.
Thus GSE might be potentially used as a chemotherapeutic drug to treat patients with acute and chronic myelogenous leukemia.
61) Int J Mol Med. 2005 Mar;15(3):539-43.
Gleditsia
sinensis fruit extract-induced apoptosis involves changes of reactive
oxygen species level, mitochondrial membrane depolarization and caspase 3
activation. Chui CH1, Lau FY, Chan AS, Cheng GY, Wong RS, Lai KB, Kok SH, Yeung TT, Teo IT, Yau MY, Cheung F, Cheng CH, Tang JC.
Recently, we have shown that the anomalous fruit extract of Gleditsia
sinensis (GSE) processes apoptotic activity on numerous solid tumour and
leukaemia cell lines as well as primary cultured leukaemia cells
obtained from bone marrow aspirate of patients. GSE treated cancer cells
exhibited apoptotic features as readily illustrated by morphological
investigation, DNA fragmentation analysis and TUNEL labelling methods.
Elevation of intracellular superoxide dismutase activity was observed.
However, the detailed mechanism still remains undefined. Here we further
demonstrated that cell cycle arrest, increment of hydrogen peroxide
production, changes of intracellular acid-base equilibrium and
mitochondrial membrane potential depolarization (DeltaPsi(m)) were
induced from cancer cells after GSE incubation. Caspase 3 protease
activity was significantly enhanced upon GSE treatment. Taken together, a
defined signaling pathway for the mechanistic action of GSE on cancer
cells was worked out.
—————————————————-
Ivermectin
62) Sharmeen, Sumaiya, et al. “
The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.” Blood 116.18 (2010): 3593-3603.
To identify known drugs with previously unrecognized anticancer
activity, we compiled and screened a library of such compounds to
identify agents cytotoxic to leukemia cells. From these screens, we
identified ivermectin, a derivative of avermectin B1 that is licensed
for the treatment of the parasitic infections, strongyloidiasis and
onchocerciasis, but is also effective against other worm infestations.
As a potential antileukemic agent,
ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines
and primary patient samples preferentially over normal hematopoietic
cells. Ivermectin also delayed tumor growth in 3 independent mouse
models of leukemia at concentrations that appear pharmacologically
achievable. As an antiparasitic, ivermectin binds and activates chloride
ion channels in nematodes, so we tested the effects of ivermectin on
chloride flux in leukemia cells. Ivermectin increased intracellular
chloride ion concentrations and cell size in leukemia cells. Chloride
influx was accompanied by plasma membrane hyperpolarization, but did not
change mitochondrial membrane potential. Ivermectin also increased
reactive oxygen species generation that was functionally important for
ivermectin-induced cell death. Finally,
ivermectin synergized with cytarabine and daunorubicin
that also increase reactive oxygen species production. Thus, given its
known toxicology and pharmacology, ivermectin could be rapidly advanced
into clinical trial for leukemia.
63) Draganov, Dobrin, et al. “
Modulation
of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin
induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).
64) Furusawa, Shinobu, et al. “Potentiation of Doxorubicin‐Induced
Apoptosis of Resistant Mouse Leukaemia Cells by Ivermectin.” Pharmacy
and Pharmacology Communications 6.3 (2000): 129-134.
65) Melotti, Alice, et al. “
The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.
Patent – Ivermectin used with chemotherapy for lymphoma
66)
Use of synergistic combinations of an avermectin and an antineoplastic compounds for the treatment of hematological malignancies
EP 2498785 A1 (text from WO2011054103A1)
The disclosure relates to a method of treating a hematological
malignancy comprising administering to a subject in need thereof a
synergistic combination of a first compound comprising an effective
amount of one or more
Avermectins and a second compound
comprising a chemotherapeutic, preferably daunorubicin, cyarabine,
doxorubicin, idarubicin mitoxantrone, amsacrine, and mixtures thereof
67) FURUSAWA SHINOBU ET AL:
“Potentiation of doxorubicin-induced apoptosis of resistant mouse leukaemia cells by ivermectin”, PHARMACY AND PHARMACOLOGY COMMUNICATIONS, vol. 6, no. 3, March 2000 (2000-03), pages 129-134, XP9167795, ISSN: 1460-8081
68) YURI N. KORYSTOV ET AL: “Avermectins inhibit multidrug resistance
of tumor cells”, EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 493, no. 1-3, 1
June 2004 (2004-06-01), pages 57-64, XP055055776, ISSN: 0014-2999,
———————————————————-
Diclofenac
69) The COX inhibitor, diclofenac induces mantle cell lymphoma
apoptosis independent of p53 status. Hesham M. Hassan1, Michelle L.
Varney2, Aalia M. Aly3, Shantaram S. Joshi2, Rakesh K. Singh2, and
Bhavana J. Dave2
Author Affiliations 1Assiut University, Assiut, Egypt;
2university of Nebraska Medical Center, Omaha, NE;
3South Egypt Cancer institute, Assiut, Egypt.
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA
Abstract
Mantle cell lymphoma (MCL) is characterized by
a clinically aggressive course with frequent relapses and poor
survival. The p53 pathway is frequently dysregulated and p53 status
predicts clinical outcome in MCL. Diclofenac has been reported to
increase p53 pathway activity, upregulates p73 expression and inhibit
cell growth; hence we investigated the ability of diclofenac to induce
apoptosis and/or cell cycle arrest in MCL, and its dependence on p53
status. To investigate the response of MCL to diclofenac, wild-type p53
[Granta-519 and JVM-2] and mutant p53 [Jeko-1 and Mino-1] expressing
cells, therapy resistant cell lines and primary human cells isolated
from MCL patients were used. Cell proliferation, apopotosis, and
expression of down-stream signaling p53 targets were analyzed. Nontoxic
concentrations of diclofenac induced concentration- and
duration-dependent inhibition of MCL cell growth independent of p53
status. Diclofenac treatment also resulted in cell cycle arrest and cell
death. Molecularly, diclofenac treatment was associated with increased
activity of caspases 3, 7, and 8. Increased p53 pathway activity was
demonstrated by duration-dependent induction of p53 transcriptional
target genes, including the cell cycle regulatory molecule p21 and
pro-apoptotic molecules including, PUMA, NOXA, BIM, and CD95. Most
importantly, diclofenac treatment was associated with enhanced
expression of the pro-apoptotic isoforms of the p53 homologue TAp73. Our
data demonstrates that diclofenac treatment results in decreased cell
cycle progression, and increased apoptosis that is associated with
increased p53 pathway activity, independent of p53 status, and increased
activity of its family member p73.
======================================================================================
Crowd Funding
70)
Can Artesunate, an antimalarial drug, provide an effective and affordable treatment for Bowel Cancer ? By Professor Sanjeev Krishna
(71) Krishna, Sanjeev, et al. “
A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer.” EBioMedicine 2.1 (2015): 82-90.
This was a single centre, randomised, double-blind,
placebo-controlled trial. Patients planned for curative resection of
biopsy confirmed single primary site Colo-rectal Cancer (CRC) were
randomised (n = 23) to receive preoperatively either 14 daily doses of
oral artesunate (200 mg;
n = 12) or placebo (
n = 11).
During a median follow up of 42 months 1 patient in the artesunate
and 6 patients in the placebo group developed recurrent CRC. Till this
analysis, there have been
no deaths in artesunate recipients (despite some patients having relatively poor prognosis), and 3 deaths in placebo recipients.
Animal Study – Veterinary Medicine Whole leaf extract 30:1 artemesia
72) Breuer, Elmar, and Thomas Efferth. “
Treatment of iron-loaded veterinary sarcoma by Artemisia annua.” Natural products and bioprospecting 4.2 (2014): 113-118.
Veterinary Clinic for Pets, Müllheim/Baden, Germany Department of
Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes
Gutenberg University, Mainz, Germany
1:30 A.annua extract for the treatment of spontaneous tumors and dogs and cats
This indicates that adjuvant iron-triggered A.annua impacts the overall
survival rates of dogs suffering from sarcoma and improves the treatment
success over that of surgery alone.
An interesting result was that artemisinin represented only a minor
constituent in A.annua and that scopoletin was the most abundant
phytochemical. It is well known that A.annua contains a large panel of
different secondary metabolites, including scopoletin, which are
cytotoxic [5, 57, 76–79]. The activity of the A.annua preparation in pet
tumors and the presence of large amounts of scopoletin raise the
question of whether scopoletin might contribute to the anticancer effect
of this plant rather than artemisinin. The in vitro cytotoxicity of
scopoletin towards cancer cells has been previously described [80–82].
Verterinary Artemsinin
73)
LupArte – Artemisia Annua Extrakt 30:1
Einzelfuttermittel mit Zusatzstoff für Hunde und Katzen
pro 450 mg- Kapsel: Aromastoff 450 mg konzentrierten Artemisia Annua
Pulverextrakt (30:1), prebiotisches Inulin aus Artischockenherzen (50
mg)
—————————————
Targeting progenitor cells Parthenolide (Feverfew)
74) Guzman, Monica L., et al. “
The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.”
Blood 105.11 (2005): 4163-4169. Recent studies have described
malignant stem cells as central to the initiation, growth, and potential
relapse of acute and chronic myelogenous leukemia (AML and CML).
Because of their important role in pathogenesis, rare and biologically
distinct leukemia stem cells (LSCs) represent a critical target for
therapeutic intervention. However, to date, very few agents have been
shown to directly target the LSC population. The present studies
demonstrate that
parthenolide (PTL), a naturally
occurring small molecule, induces robust apoptosis in primary human AML
cells and blast crisis CML (bcCML) cells while sparing normal
hematopoietic cells. Furthermore, analysis of progenitor cells using in
vitro colony assays, as well as stem cells using the nonobese
diabetic/severe combined immunodeficient (NOD/SCID) xenograft model,
show that PTL also preferentially targets AML progenitor and stem cell
populations. Notably, in comparison to the standard chemotherapy drug
cytosine arabinoside (Ara-C), PTL is much more specific to leukemia
cells.
The molecular mechanism of PTL-mediated apoptosis is
strongly associated with inhibition of nuclear factor κ B (NF-κB),
proapoptotic activation of p53, and increased reactive oxygen species
(ROS). On the basis of these findings, we propose that the
activity of PTL triggers LSC-specific apoptosis and as such represents a
potentially important new class of drugs for LSC-targeted therapy.
Parthenolide (PTL) is a sesquiterpene lactone found as the major
active component in Feverfew (Tanacetum parthenium), an herbal medicine
that has been used to treat migraine and rheumatoid arthritis for
centuries.12 More recently, PTL has been found to have several other
properties, including antitumor activity, inhibition of DNA synthesis,
and inhibition of cell proliferation in different cancer cell
lines.13-16 In addition, PTL sensitizes cancer cells to other antitumor
agents17-20 and acts as a chemopreventive agent in a UVB-induced skin
cancer animal model.21 PTL is a potent inhibitor of NF-κB activation and
has been shown to directly bind IκB-kinase (IKK)22,23 and to modify the
p50 and p65 NF-κB subunits.24,25 PTL can also block signal transducers
and activators of transcription 3 (STAT3) phosphorylation on Tyr705,26
sustain c-Jun N-terminal kinase (JNK) activation,17,18 and increase
intracellular reactive oxygen species (ROS).13,27
Targeting cancer stem cells
75) Naujokat, Cord, and Roman Steinhart. “
Salinomycin as a Drug for Targeting Human Cancer Stem Cells.” Journal of Biomedicine and Biotechnology 2012 (2012).
In particular, the biomolecules
salinomycin and parthenolide as well as the biguanide
metformin
have been demonstrated to induce apoptosis in various types of human
cancer cells [108, 123, 124], suggesting that these compounds may
contribute to the eradication of cancer more effectively than compounds
targeting either CSCs or regular cancer cells. Moreover, the
ionophore antibiotic salinomycin
seems to have even extended capabilities of eliminating cancer (Table
1), because this compound has been demonstrated to effectively target
regular cancer cells [16, 125–127], highly multidrug and
apoptosis-resistant cancer cells [16, 85, 125], and CSCs [16, 84, 87,
88, 128–131].
——————-
synergy artemisinin with butyrate
76) Anticancer Res. 2005 Nov-Dec;25(6B):4325-31.
Synergistic cytotoxicity of artemisinin and sodium butyrate on human cancer cells.Singh NP1, Lai HC.
Butyric acid is a short chain fatty acid produced by large bowel
bacterial flora. It serves as an antiinflammatory agent and nutrient for
normal colon cells. Butyric acid has also been shown to induce
apoptosis in colon and many other cancer cells. Artemisinin is a
compound extracted from the wormwood Artemisia annua L. It has been
shown to selectively kill cancer cells in vitro and to be effective in
treating animal and human cancer. We and others have found that the
artemisinin analog, dihydroartemisinin (DHA), kills cancer cells by
apoptosis. In the present study, the efficacy of a combined treatment of
DHA and butyric acid at low doses in killing cancer cells was
investigated.
MATERIALS AND METHODS:Molt-4 cells (a human
lymphoblastoid leukemia cell
line) and freshly isolated human lymphocytes, cultured in complete
RPMI-1640 medium, were first incubated with 12 microM of human
holotransferrin at 37 degrees C in a humid atmosphere of 5% CO2 for one
hour to enhance the iron concentration in the cells. Cells from each
cell type were then divided into 20 flasks. These flasks were grouped
into four sets of five cultures each. Zero, 5, 10 or 20 microM of DHA
was added, respectively, to these sets and the cells were incubated at
37 degrees C for one hour. Zero, 1, 5, 10, or 20 mM of sodium butyrate
was then added to the five cultures of each set, respectively. Thus, the
treatments involved a combination of 4 doses of DHA and 5 doses of
sodium butyrate. The cells were counted immediately before the addition
of DHA, and at 24 and 48 hours after the addition of sodium butyrate.
RESULTS:DHA alone at the 24-hour time-point and 20 microM concentration
significantly reduced the number of Molt-4 cells in the culture by
approximately 40% (p < 0.001, compared to non-treated control),
whereas it did not significantly affect the number of normal human
lymphocytes. Similarly, 1 mM sodium butyrate alone at 24 hours reduced
the number of Molt-4 cells by approximately 32% (p < 0.001, compared
to non-treated control), without significantly affecting normal human
lymphocytes.
The combination of 20 microM DHA and 1 mM sodium
butyrate killed all Molt-4 cells at the 24-hour time-point and did not
significantly affect lymphocytes.
CONCLUSION:DHA in combination with butyric acid acts
synergistically at low doses. The combination may provide a less toxic,
inexpensive and effective cancer chemotherapy.
The oral intake of artemisinin and its analogs (7, 43) and butyric
acid (44) is safe. Oral administration of the artemisinin analogs,
artesunate (100 mg in a healthy adult) resulted in micromolar plasma
concentration of DHA (45). The basal plasma concentration of butyric
acid is normally >1 ÌM (42). Oral or intravenous administration of
sodium butyrate (50 mg/kg) has been shown to increase the plasma
butyrate concentration to the millimolar range in rats (46).
The artemisinin-butyrate combination may work well, particularly for
colon cancer where butyrate concentrations can be raised by simple oral
probiotic intake of butyric acid producing Lactobacilli.
Artemisinin Synergy with Rituximab anti-CD-20 Ab
77) Sieber, Sebastian, et al. “Combination treatment of malignant B cells using the anti-CD20 antibody
rituximab and the anti-malarial
artesunate.” International journal of oncology 35.1 (2009): 149-158.
Combination treatment of malignant B cells Rituximab and Artesunate Sieber Sebastian Int j oncology 2009
Chemotherapy of non-Hodgkin’s lymphoma is frequently hampered by drug
resistance. The monoclonal antibody rituximab specifically targets the
CD20 antigen and sensitizes B-cell lymphoma cells to standard anticancer
drugs. In the present investigation, we analyzed, whether a combination
of rituximab and artesunate may act in a complementary manner and
eventually synergize in tumor cell killing. Artesunate is an
anti-malarial drug, which also exerts profound activity towards cancer
cells. While rituximab alone was minimally cytotoxic, rituximab
increased cytotoxicity to artesunate in Ramos cells. Artesunate induced
apoptosis, induced Fas/CD95 expression and the formation of reactive
oxygen species (ROS) and resulted in a breakdown of mitochondrial
membrane potential. This argues for the involvement of both
receptor-driven extrinsic and mitochondrial intrinsic routes of
apoptosis. Rituximab increased Fas/CD95 expression and ROS formation and
decreased mitochondrial membrane potential ultimately leading to
increased apoptosis induced by artesunate. The transcription factors YY1
and Sp1 are upstream regulators of apoptosis by controlling the
expression of apoptosis-regulating genes. YY1 and Sp1 were
down-regulated and Fas/CD95 was up-regulated by rituximab and artesunate
indicating that artesunate activated the Fas/CD95 pathway and that
rituximab increased the susceptibility of tumor cells to
artesunate-induced apoptosis. Furthermore, rituximab affected the
expression of antioxidant genes. The antibody decreased
artesunate-induced up-regulation of catalase expression and increased
artesunate-induced down-regulation of glutathione S-transferase-phi
expression. Manganese-dependent superoxide dismutase expression was not
changed by artesunate. Antioxidant proteins may help to detoxify
artesunate-induced ROS. Rituximab reversed the artesunate-induced
expression changes of antioxidant genes and, hence, reduced the
detoxification capacity of Ramos cells. The effects of rituximab on
antioxidant genes represent a novel mechanism of rituximab for
chemosensitization.
Lymphoma and Myeloma Highly Sensitive to Artemisinin
78) Eur J Haematol. 2013 Oct;91(4):339-46.
Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate.
Holien T1, Olsen OE, Misund K, Hella H, Waage A, Rø TB, Sundan A.
The use of new drugs has improved the treatment of multiple myeloma
and diffuse large B-cell lymphoma (DLBCL). Nevertheless, over time many
patients relapse and develop resistance to treatment, and efforts are
needed to overcome drug resistance. The widely used malaria drug
artesunate has been reported to have antitumor activity, and we aimed to
test the effects of artesunate on a panel of
myeloma and lymphoma cells.
METHODS:Myeloma and DLBCL cell lines were treated with artesunate in
vitro. The effects of artesunate treatment were evaluated using ATP
content measurements for proliferation and annexin V/propidium iodide
labeling for apoptosis. Western blotting was used to look for
artesunate-induced protein changes. In addition, we measured artesunate
effects on patient myeloma cells in the presence of bone marrow stromal
cells.
RESULTS:Artesunate treatment efficiently inhibited cell growth and
induced apoptosis in cell lines. Apoptosis was induced concomitantly
with downregulation of MYC and anti-apoptotic Bcl-2 family proteins, as
well as with cleavage of caspase-3.
The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 μm.
Furthermore, some primary myeloma cells were also sensitive to
artesunate at doses around 10 μm. Concentrations of this order are
pharmacologically relevant as
they can be obtained in plasma after intravenous administration of artesunate for malaria treatment.
CONCLUSION:Our findings indicate that artesunate is a potential drug for
treatment of multiple myeloma and DLBCL at doses of the same order as
currently in use for treatment of malaria without serious adverse
effects.
Use of Vitamins interacting with Artemisinin
Vitamin C, Vit D, H202 potentiates artemisinin leukemia cell death.
NOT vit E. though.
79) Anticancer Res. 2015 Apr;35(4):1867-71. Effects of antioxidants
and pro-oxidants on cytotoxicity of dihydroartemisinin to Molt-4 human
leukemia cells. Gerhardt T1, Jones R1, Park J1, Lu R1, Chan HW1, Fang
Q1, Singh N2, Lai H1.
Antioxidants and Pro oxidants cytotoxicity of dihydroartemisinin to leukemia cells Gerhardt Anticancer Res 2015
The objective of the present study was to investigate how oxidative
status influences the effectiveness of cytotoxicity of artemisinin
towards cancer cells. It is hypothesized that antioxidants would reduce,
whereas pro-oxidants would enhance, cytotoxicity.
MATERIALS AND METHODS:Molt-4 human leukemia cells were incubated with
vitamins C, E, D3, dexamethasone, or hydrogen peroxide
alone or in combination with dihydroartemisinin (DHA). Concentrations
of these compounds studied were similar to those achievable by oral
administration. Viable cell counts were performed before (0 h) and at,
24 and 48 h after treatment.
RESULTS:Vitamin C, vitamin D3, dexamethasone, and H2O2 caused
significant Molt-4 cell death. Vitamin E caused an increase in Molt-4
cell growth.
Vitamin C and vitamin D3 significantly interacted
with DHA at the 48-h time point and with H2O2 at both 24-h and 48-h time
points.
CONCLUSION:Cellular oxidative status could alter the potency of artemisinin in killing cancer cells.
80) Hamacher-Brady, Anne, et al. “Artesunate Activates Mitochondrial
Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive
Oxygen Species Production.” J. Biol. Chem 2011.286 (2010): 6587-6601.
Artesunate
Activates Mitochondrial Apoptosis in Breast Cancer Cells via
Iron-catalyzed Lysosomal Reactive Oxygen Species Production J Biol Chem
2011 Hamacher Brady
We thus investigated the role of lysosomes in ART-induced PCD and
determined that in MCF-7 breast cancer cells ART activates
lysosome-dependent mitochondrial outer membrane permeabilization. ART
impacted endolysosomal and autophagosomal compartments, inhibiting
autophagosome turnover and causing perinuclear clustering of
autophagosomes, early and late endosomes, and lysosomes.
Lysosomal iron chelation blocked all measured parameters of ART-induced PCD, whereas lysosomal iron loading enhanced
death, thus identifying lysosomal iron as the lethal
source of reactive oxygen species upstream of mitochondrial outer
membrane permeabilization
Moreover,
lysosomal inhibitors chloroquine and bafilomycin A1 reduced ART-activated PCD, evidencing a requirement for lysosomal function during PCD signaling.
CQ
(chloroquin) resulted in enhanced vesicle size and LTR intensity,
consistent with previously reported CQ-induced increase in lysosomal activities (44, 45).
The malaria parasite digests iron-rich hemoglobin in its acidic food
vacuole, and the interaction of ART with hemederived iron results in
lethal ROS generation (15).
The parasite food vacuole is analogous to eukaryotic lysosomes,
organelles that constitute a major site of intracellular degradation
via hydrolytic enzymes. Therefore, we investigated the role of lysosomal
iron in ART-activated ROS production and PCD in MCF-7 cells by
employing the
iron chelator deferoxamine mesylate (DFO). DFO specifically targets lysosomal iron as it enters the cell via endocytosis and accumulates in the lysosome (37).
In combination with ART, DFO decreased ART-triggered ROS production, with a
significant difference for ART at 20 g/ml. Moreover, at 48 h
DFO significantly decreased ART-induced cell death to the levels of DFO alone at ART concentrations of both 10 and 20 g/ml.
Endolysosomal Iron Loading Enhances ART-triggered PCD
We employed diferric holotransferrin (HTF), which is actively
internalized by receptor-mediated endocytosis; during transit through
endolysosomes, bound iron is released due to low pH environment (18)
HTF (holotransferrin) co-treatment with both 10 and 20 g/ml ART
significantly increased cell death
at 24 h and at 48 h (Fig. 2C). The ensemble of findings given above
indicates that lysosomal free iron serves as the major source of ROS and
thereby is a critical prerequisite during ART-mediated cell death in
MCF-7 breast cancer cells. In response to both ART 10 g/ml and ART 20
g/ml,
AVs were clustered to the perinuclear region (Fig. 3A, arrows). DFO (iron chelator) treatment prevented AV clustering in response to ART.
———–
81) Yang, Nai-Di, et al. “
Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin.” Journal of Biological Chemistry 289.48 (2014): 33425-33441. full free
Here, we utilized a blue fluorescence-tagged ART to investigate its
localization, and our results clearly showed that ART accumulates in
lysosome.
The addition of antioxidant
N-acetylcysteine (NAC), which has been shown to directly react with hydrogen peroxide and superoxide (40), was able to
inhibit the production of ROS induced by ART
As expected, both
NAC and BAF (Baflinomycin) significantly protected ART-induced cell death (Fig. 6E).
In summary, these data indicate that lysosomal iron plays a critical
role in ART-induced lysosomal activation, mitochondrial ROS production,
and cell death. These results thus indicate that
ART-induced ferritin degradation is mainly performed by the lysosomes.
Altogether, these data suggest that it is not the lysosomes per se required for ART-induced cell death, but
delivery and degradation of ferritin in lysosomes is required for ART-induced cell death.
First, ART accumulates in the lysosomes (Fig. 2); second, ART
increases lysosomal acidification, cathepsin enzyme activity, and
protein degradation via promoting lysosomal V-ATPase assembly . At
present, the exact mechanism for the lysosomal accumulation by ART is
not known. ART may increase lysosomal V-ATPase activity via promoting
the assembly status of the two domains.
we believe that this perinuclear clustering of lysosomes is, in fact, an indication of autophagy induction.
the endoperoxide bridge of ART is broken by ferrous iron, and then ART
becomes free radicals to target cellular organelles, such as
mitochondria, and eventually leads to cell death
In fact, we also found that
chloroquine inhibited the ferritin degradation and cell death induced by ART as efficiently as BAF (data not shown).
In summary, we demonstrate a novel mechanism underlying ART-induced cancer cell death. As shown in Fig. 9E,
ART
accumulates in lysosomes and reacts with lysosomal iron. The activated
ART then promotes lysosomal function via enhancing V-ATPase assembly.
One major source of iron for the cytotoxicity of ART is attained from
the degradation of ferritin by lysosomes. In conclusion, we
propose a new model of action on the mechanism of ART-induced cell death
by focusing on lysosomal activation and ferritin degradation. At
present, there is evidence demonstrating
higher iron levels in cancer cells than in non-cancerous cells,
and iron has been targeted for cancer therapy and prevention (69).
Therefore, the results from our study support the development of this
important anti-malaria drug as a cancer therapeutic agent.
82) Lai, Henry, et al. “Effects of artemisinin-tagged holotransferrin on cancer cells.” Life sciences 76.11 (2005): 1267-1279.
83) Int J Pharm. 2008 Apr 16;354(1-2):28-33. Epub 2007 Sep 6.
Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Nakase I1, Lai H, Singh NP, Sasaki T.
Artemisinin and its derivatives are well known antimalaria drugs and
particularly useful for the treatment of infection of Plasmodium
falciparum malaria parasites resistant to traditional antimalarials.
Artemisinin has an endoperoxide bridge that is activated by
intraparasitic heme-iron to form free radicals, which kill malaria
parasites by alkylating biomolecules. In recent years, there are many
reports of anticancer activities of artemisinins both in vitro and in
vivo. Artemisinins have inhibitory effects on cancer cell growth,
including many drug- and radiation-resistant cancer cell lines. The
cytotoxic effect of artemisinin is specific to cancer cells because most
cancer cells express a high concentration of transferrin receptors on
cell surface and have higher iron ion influx than normal cells via
transferrin mechanism. In addition, some artemisinin analogs have been
shown to have antiangiogenesis activity. Artemisinin tagged to
transferrin via carbohydrate chain has also been shown to have high
potency and specificity against cancer cells. The conjugation enables
targeted delivery of artemisinin into cancer cells. In this review, we
discuss the anticancer activities and mechanisms of action of
artemisinins and the transferrin-conjugate.
mitochondrial outer membrane permeabilization (MOMP).'[
84) Lai, Henry, et al. “
Artemisinin-transferrin conjugate retards growth of breast tumors in the rat.”
Anticancer research 29.10 (2009): 3807-3810. Artemisinin can retard
cancer growth but not completely stop or reduce the growth. This is
shown by the data of this experiment on breast cancer and on
fibrosarcoma in rats reported previously by us (18). In most studies on
the effect of artemisinin analogs on tumor growth in animals, an
approximately 20-60% reduction in growth was generally observed in
colorectal carcinoma xenografts (19), hepatoma xenograft (20), ovarian
cancer (21), and HL-60 human leukemia xenograft (22). Exceptions are a
study by Willoughby et al. (23) in which a complete elimination of
prostate cancer xenograft in mice was reported after treatment with
artemisinin, and that of Wang et al. (24) in which no significant effect
on the growth of implanted Lewis lung cancer in mice was found with
artemisinin treatment.
Once the tumor is established,
artemisinin is not very effective in reversing the progress. However,
artemisinin is effective in the prevention of cancer when the target
cells are still small in number.
85) Mariani, A., et al. “
Iron-dependent lysosomal dysfunction mediated by a natural product hybrid.” Chemical Communications 52.7 (2016): 1358-1360.
Artesumycin is a fluorescent hybrid of the natural products marmycin A
and artemisinin. It was designed to combine the lysosomotropic
properties of the angucycline and the iron-reactive capacity of the
endoperoxide to target the lysosomal compartment of cancer cells.
Herein, we show that artesumycin inhibits cancer cell proliferation in
an iron-dependent manner and chemically fragments in vitro in the
presence of redox-active iron(II). Visual detection of artesumycin by
fluorescence microscopy provided substantial evidence that the
small molecule selectively targets lysosomes.
This original approach based on a fluorescent and iron-reactive probe
represents a powerful strategy for initiating and, concomitantly,
visualizing lysosomal dysfunction in human cells.
(86) Yu, Zuoren, et al. “
Cancer stem cells.” The international journal of biochemistry & cell biology 44.12 (2012): 2144-2151.
87) Yu, Zuoren, et al. “
Cancer stem cells.” The international journal of biochemistry & cell biology 44.12 (2012): 2144-2151.
88) Pardal, Ricardo, Michael F. Clarke, and Sean J. Morrison.
“APPLYING THE PRINCIPLES OF STEM-CELL BIOLOGY TO CANCER.” NATURE
REVIEWS| CANCER 3 (2003): 895.
APPLYING THE PRINCIPLES OF STEM-CELL BIOLOGY TO CANCER. Pardal 2003
(89) Hsieh, Hsiu-Mei, et al. “
Berberine-containing
pharmaceutical composition for inhibiting cancer stem cell growth or
carcinoma metastasis and application thereof.” U.S. Patent Application No. 14/790,154.
90) Moselhy, J., et al. “
Natural Products That Target Cancer Stem Cells.” Anticancer research 35.11 (2015): 5773.
Epigallocatechin-3-gallate (EGCG) – Green Tea
6-Gingerol – Ginger
β-Carotene – Carrot, Leafy Greens
Baicalein – Chinese Skullcap
Curcumin – Turmeric
Cyclopamine – Corn Lilly
Delphinidin – Blueberry, raspberrry
Flavonoids (Genistein) – Soy, red clover, coffee
Gossypol – Cottonseed
Guggulsterone – Commiphora (myrrh tree)
Isothiocyanates – Cruciferous vegetables
Linalool – Mint
Lycopene – Grapefruit, tomato
Parthenolide – Feverfew
Perylill alcohol – Mint, cherry, lavender
Piperine – Black pepper
Placycodon saponin – Playycodon grandifloruim
Psoralidin – Psoralea corylilyfolia
Quercetin – Capers, onion
Resveratrol – Grapes, plums, berries
Salinomycin – Streptomyces albus
Silibinin – Milk Thistle
Ursolic acid – Thyme, basil,
oregano
Vitamin D3 – Fish, egg yolk, beef, cod liver oil
Withaferin A – Withania somnifera (ashwaganda)
91) Naujokat, Cord, and Roman Steinhart. “Salinomycin as a drug for
targeting human cancer stem cells.” BioMed Research International 2012
(2012).
Salinomycin as a drug for targeting human cancer stem cells 2012 Naujokat Cord Steinhart
——————–
Feverfew Parthenolide
92) Ghantous, Akram, et al. “What made sesquiterpene lactones reach cancer clinical trials?.”
What made sesquiterpene lactones reach cancer clinical trials Ghantous Akram 2010. Drug discovery today 15.15 (2010): 668-678.
Medicinal plants, rich in SLs and having anti-inflammatory properties, are a potential source of NFkB inhibitors [48].
Parthenolide and artemisinin are established NF-kB inhibitors and render cancer cells sensitive to chemotherapy
[49,55]. Parthenolide was found to directly modify the NF-kB p65 subunit
[58] or to suppress the activity of the upstream IkB kinase complex
leading to the stabilization of the NF-kB inhibitors, IkBa and IkBb
[59]. The nucleophilic attack by parthenolide occurs through
a-methylene-g-lactone ring and epoxide and epoxide moieties that target
specific nucleophiles but not others [60].
Parthenolide is the only small molecule, to date, that has been
reported to selectively target several cancer and cancer stem cells
while sparing normal counterparts [28,38,69]. NF-kB signaling is
elevated in leukemic stem cells
but not in the normal hematopoietic stem cells. Parthenolide caused robust apoptosis of primary AML cells and
effectively eradicated AML stem and progenitor cells in vitro without affecting hematopoietic stem cells [28,69]. The mechanism of action of parthenolide was found to be through the
inhibition of NF-kB, the activation of proapoptotic p53 and an increase in reactive
oxygen species [69]. Gleevec or
Cytarabine,
treatments commonly used for the most aggressive leukemias, are not as
effective as parthenolide because they are not as specific.
Promising antileukemic drugs should mediate cell death and inhibit
leukemic stemcell- specific activity, and parthenolide fulfills these
criteria
Parthenolide Phase I trial – No blood levels found ??
93) Invest New Drugs. 2004 Aug;22(3):299-305.
Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer. Curry EA 3rd1, Murry DJ, Yoder C, Fife K, Armstrong V, Nakshatri H, O’Connell M, Sweeney CJ.
Feverfew is a botanical product that contains parthenolide.
Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic
activity. Feverfew has been used extensively without any formal
pharmacokinetic analysis. A Phase I trial was conducted to evaluate the
pharmacokinetics and toxicity of parthenolide given as a component of
“feverfew.”
PATIENTS AND METHODS:Feverfew (Tanacet trade mark ) was administered as a
daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day
was explored with subsequent dose escalations to 2, 3, and 4 mg.
Assessment of plasma pharmacokinetics was performed on patients accrued
to the trial. Solid phase extraction and mass spectroscopy were used to
evaluate parthenolide plasma concentrations. The limit of detection for
parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for
response after every two cycles.
RESULTS:Feverfew given on this schedule had no significant toxicity, and
the maximum tolerated dose was not reached. When parthenolide was
administered at doses up to
4 mg as a daily oral capsule in the feverfew preparation, there was
not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed.
CONCLUSION:Feverfew, with up to 4 mg of parthenolide, given daily as an
oral tablet is well tolerated without dose- limiting toxicity, but does
not provide detectable plasma concentrations. Purification of
parthenolide for administration of higher doses will be needed.
94) full pdf
GUNN, ELLEN J., et al. “The natural products parthenolide and
andrographolide exhibit anti-cancer stem cell activity in multiple
myeloma.”
The
natural products parthenolide and andrographolide exhibit anti-cancer
stem cell activity in multiple myeloma Ellen Gunn 2011. Leukemia & Lymphoma 52.6 (2011): 1085-1097.
Abstract Multiple myeloma (MM) is an incurable plasma cell malignancy where
nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor,
leaving the cancer stem cells to trigger a relapse.
Utilizing a three-dimensional tissue culture system where cells were
grown in extracellular matrix designed to reconstruct human bone
marrow, we tested the anti-multiple myeloma cancer stem cell (MM-CSC)
potential of two natural product inhibitors of nuclear factor kB (NFkB).
Here we show that
parthenolide and andrographolide are potent anti-MMCSC
agents. Both natural products demonstrated preferential toxicity toward
MM-CSCs over non-tumorigenic MM cells. Addition of the bone marrow
stromal compartment abrogated andrographolide activity while having no
effect on
parthenolide cytoxicity. This is the first report of a natural product
with anti-CSC activity in myeloma, suggesting that it has the potential
to improve the survival of patients with MM by eliminating the
relapse-causing MM-CSCs.
Crooks PA
95) Bioorg Med Chem Lett. 2009 Aug 1;19(15):4346-9. .
Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-kappaB inhibitor, DMAPT (LC-1). Neelakantan S1, Nasim S, Guzman ML, Jordan CT,
Crooks PA.
A series of aminoparthenolide analogs (6-37) were synthesized and
evaluated for their anti-leukemic activity. Eight compounds exhibited
good anti-leukemic activity with LD(50)’s in the
low microM range (1.5-3.0microM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than
90% cell death at 10microM concentration against primary AML cells in culture, with LD(50) values of 1.7, 1.8 and 1.6microM.
96) Zhang, Quan, et al. “
Guaianolide
sesquiterpene lactones, a source to discover agents that selectively
inhibit acute myelogenous leukemia stem and progenitor cells.” Journal of medicinal chemistry 55.20 (2012): 8757-8769.
97) Shanmugam, Rajasubramaniam, et al. “
A
water soluble parthenolide analog suppresses in vivo tumor growth of
two tobacco‐associated cancers, lung and bladder cancer, by targeting
NF‐κB and generating reactive oxygen species.”
98) International Journal of Cancer 128.10 (2011): 2481-2494.
Karmakar, A., et al. “
Nanodelivery of parthenolide using functionalized nanographene enhances its anticancer activity.” RSC advances 5.4 (2015): 2411-2420.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
full free
99) J Biol Chem. 2013 November 22; 288(47): 33542–33558.
Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells* Shanshan Pei,‡
Our data indicate that CD34+ AML cells have
elevated expression of multiple glutathione pathway regulatory proteins,
presumably as a mechanism to compensate for increased oxidative stress
in leukemic cells. Consistent with this observation, CD34+ AML cells
have lower levels of reduced glutathione and increased levels of
oxidized glutathione compared with normal CD34+ cells. These findings
led us to hypothesize that AML cells will be
hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as
parthenolide (PTL) or piperlongumine that
induce almost complete glutathione depletion and severe cell death in CD34+ AML cells.
Importantly, these compounds only induce limited and transient
glutathione depletion as well as significantly less toxicity in normal
CD34+ cells. We further determined that PTL perturbs glutathione
homeostasis by a multifactorial mechanism, which includes inhibiting key
glutathione metabolic enzymes (GCLC and GPX1), as well as
direct depletion of glutathione.
These findings demonstrate that primitive leukemia cells are uniquely
sensitive to agents that target aberrant glutathione metabolism, an
intrinsic property of primary human AML cells. Our findings indicate
agents such as
parthenolide (PTL) and piperlongumine (PLM) have a dramatic inhibitory effect on the leukemic glutathione system, whereas
only a limited and transient perturbation in normal cells.
This preferential effect is strongly linked to their selective toxicity
toward leukemia and other cancer cell types. Importantly, we have
previously shown that PTL effectively eradicates AML stem and progenitor
populations (11), cells that are typically resistant/refractory to
conventional chemotherapy (12, 13).
Thus, we propose that therapeutic targeting of glutathione metabolism
represents a potentially powerful strategy to induce selective toxicity
toward a broad range of primary leukemia cells, including malignant
stem and progenitor populations.
We first studied PTL, which contains an
active α,β-unsaturated-γ-lactone group (Fig. 3B, red circular area) that should readily react with the free thiol group of glutathione. Indeed,
PTL induced a dose-dependent decrease of cellular glutathione within 2 h of treatment in primary AML cells
!!!!!!!!!!!!!!!!!!!!!!!
Mantle cells have high glutathione transferase
100) Bennaceur-Griscelli, Annelise, et al. “
High level of glutathione-S-transferase π expression in mantle cell lymphomas.” Clinical cancer research 10.9 (2004): 3029-3034.
The GST-π gene in located at 11q13 and is coamplified with the cyclin
D1 gene (in the same amplicon) in some human solid tumors (breast
carcinoma, squamous cell lung carcinoma, bladder carcinomas, and
esophageal carcinoma; Ref. 19). The unusual resistance to chemotherapy
in MCL compared with other lymphoma entities GST-π overexpression has
been associated with resistance to alkylating agents and
anthracyclines.
A high GST-π expression (>50% cells stained) was observed in the 24 cases of MCL
MCL is one of the most chemotherapy-drug-resistant lymphomas.
The 10 patients who received sequential CHOP and cytarabine-based
chemotherapy at diagnosis did not reach complete remission after CHOP
alone but entered into complete remission after high-dose cytarabine
(38) . The modest role of the glutathione system in cytarabine
resistance compared with alkylating and anthracyclin resistance could be
an explanation for the high complete remission rate observed after
high-dose cytarabine therapy in MCL (7 , 39)
101) Zhou, Jianbiao, and Wee-Joo Chng. “Identification and targeting
leukemia stem cells:The path to the cure for acute myeloid leukemia.”
World J Stem Cells 6.4 (2014): 473-484.
Identification and targeting leukemia stem cellsThe path to the cure for acute myeloid leukemia Zhou 2014
full pdf
102) FOLIA HISTOCHEMICA ET CYTOBIOLOGICA Vol. 46, No. 2, 2008
pp. 129-135. Molecular basis of parthenolide-dependent proapoptotic
activity in cancer cells Beata Paj¹k1, Arkadiusz Orzechowski1,2,
Barbara Gajkowska1
1Department of Cell Ultrastructure, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland 2Department
Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells Beata Pajak 2008
Saadane et al. [32] found that the inhibition of IKKβ resulted in
stabilization of cytoplasmic IKKα, which in turn leads to inhibition of
NF-κB translocation. In contrast, Hehner et al. [28] speculated that PN
interferes with IKC component that is necessary for the sequential
transmission of signals leading to the activation of both IKKs. Since
the IKC is non-functional in the absence of NK- κB essential
modulator/IKKγ, this latter protein was the potential candidate for the
inhibitory activity of parthenolide. Moreover, in all cases, the PN
administration blocked DNA-binding of NF-κB. Consequently,
lack of NF-κB activity render cancer cells prone to undergo apoptosis or became sensitized to cytokine- and anti-cancer drug-induced cell death [33-36].
PATENT
103) Use of parthenolide derivatives as antileukemic and cytotoxic agents
US 20150259356 A1
Publication number US20150259356 A1
Publication type Application
Application number US 14/727,126
Publication date Sep 17, 2015
Filing date Jun 1, 2015
Priority date Jul 11, 2003
Also published as US7678904, 9 More »
Inventors Peter A. Crooks, Craig T. Jordan, Xiaochen Wei
Original Assignee University Of Kentucky
104) Zhou, Jianbiao, Ying Qing Ching, and Wee-Joo Chng. “Aberrant
nuclear factor-kappa B activity in acute myeloid Leukemia: from
molecular pathogenesis to therapeutic target.” Oncotarget 6.8 (2015):
5490.
105) Planta Med. 2003 Nov;69(11):1009-12.
Transport of parthenolide across human intestinal cells (Caco-2).
Khan SI1, Abourashed EA, Khan IA, Walker LA.
This study examined the intestinal epithelial membrane transport of the
sesquiterpene lactone parthenolide, a bioactive compound present in the
migraine prophylactic herb feverfew. The Caco-2 human colonic cell line
was used as an in vitro model of the human intestinal mucosal barrier.
The bidirectional transport (apical to basolateral and basolateral to
apical) of parthenolide was investigated using Caco-2 monolayers grown
on Transwell inserts.
Quantitation of parthenolide was performed using high performance
liquid chromatography (HPLC). Apical to basolateral and basolateral to
apical permeability coefficients and percent transport were calculated
and a potential bioavailability of parthenolide was determined. Sodium
fluorescein was used as a marker for paracellular leakage. Parthenolide,
at a concentration of 250 microM, demonstrated substantial linear
transport across the monolayer. The transport parameters were not
affected by the presence of MK-571, an inhibitor of multidrug resistance
transporter P-glycoprotein (MRP). Upon comparison of the transport
parameters of parthenolide with atenolol under identical conditions and
the reported values for model compounds like mannitol and propranolol,
it is concluded that parthenolide is effectively absorbed through the
intestinal mucosa via a passive diffusion mechanism.
FeverFew Inhibits Platelets
106) Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115(4):447-9.
Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups. Heptinstall S1, Groenewegen WA, Spangenberg P, Lösche W.
Extracts of feverfew inhibit platelet aggregation and the platelet
release reaction. The active components are believed to be
sesquiterpene lactones such as parthenolide. Evidence is presented that
inhibition of platelet behaviour is via neutralization of sulphydryl
groups either inside or outside the cell. The precise nature of the
sulphydryl groups that are susceptible to feverfew and are involved in
platelet aggregation and the release reaction have not yet been defined.
107)
DNC NEWS:
Feverfew, Stem cells and the treatment of Cancer
June 29, 2005 Subject: Research on the common herb feverfew suggests it may play an important role in the treatment of Cancer.
PATENT
108) Stabilized feverfew formulations
WO 2005082393 A1
patent 4% feverfew
http://www.google.com/patents/WO2005082393A1?cl=en
A Feverfew extract containing 4% parthenolide is available from Galilee Herbal Remedies and as OptiPure Brand (Chemco
Industries, Inc.) as “PharmaFew”. [009] The present invention more advantageously provides a “stabilized”
Feverfew extract having at least about 4% parthenolide by weight of the
total weight of the extract. Roy Bouskila, Soft Gel Technologies Inc,
Ronald G Udell
——————————————————————-
Sulforaphane
109) Sestili, Piero, and Carmela Fimognari. “
Cytotoxic and Antitumor Activity of Sulforaphane: The Role of Reactive Oxygen Species.” BioMed Research International 2015 (2015).
SFR is passively absorbed by cells, where it is rapidly conjugated with glutathione (GSH) by glutathione S-transferases (GSTs).
However, after dietary consumption, SFR levels in humans are lower and closer to 3 μM
SFR administered orally protects against animal carcinogenesis and
induces antiproliferative effects in human tumor cells in xenograft
models.
A second important antitumor mechanism is the ability of SFR to block
cell proliferation and induce apoptosis of cancer cells, thus reducing
tumor growth.
depletes glutathione
it is important noting that cells treated with high doses of SFR
undergo a situation of increased ROS sensitivity since a peculiar
capacity of the isothiocyanate consists in depleting the GSH cellular
pool [58, 59] (Figure 1), an effect which is particularly severe with
high, supranutritional SFR concentrations. Indeed, depletion of GSH
deprives cells of a first line, soluble antioxidant defense [53, 60,
61], giving rise to a “vicious oxidative cycle” (ROS production in cells
which at the same time are being depleted in GSH) which is indirectly
demonstrated by the fact that N-acetylcysteine (NAC) supplementation
enhanced cell survival opposing to GSH depletion [57, 58] rather than
acting itself as a mere, direct antioxidant.
loss of mitochondrial transmembrane potential, release of cytochrome C, and mitochondrial damage are in effect induced by SFR
A selective toxicity of SFR to cancer cells has been demonstrated in different experimental models.
Leukemia Lymphoma
110) Fimognari C., Turrini E., Sestili P., et al.
Antileukemic
activity of sulforaphane in primary blasts from patients affected by
myelo- and lympho-proliferative disorders and in hypoxic conditions. PLoS ONE. 2014;9(7)
Sulforaphane caused a dose-dependent induction of apoptosis in
blasts from patients diagnosed with acute lymphoblastic or myeloid
leukemia.
We found that synthesized SR caused a dose-dependent induction of
apoptosis in acute leukemia cell lines and primary lymphoblasts from
patients diagnosed with B-ALL, T-ALL, and AML.
SR controlled the expansion of leukemic cells
As to the concentrations of SR used in this study, they could be not
achievable from food supply. However, after a single oral dose of SR at
150 µmol/kg in rat, plasma concentrations of SR equivalents increase to
15.2 µM [46].
111) Shang, Hung‐Sheng, et al. “
Sulforaphane‐induced
apoptosis in human leukemia HL‐60 cells through extrinsic and intrinsic
signal pathways and altering associated genes expression assayed by
cDNA microarray.” Environmental toxicology (2016).
Breast Cancer
112) Li, Yanyan, et al. “
Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells.” Clinical Cancer Research 16.9 (2010): 2580-2590.
A NOD/SCID xenograft model was employed to determine whether sulforaphane could target breast CSCs in vivo,
Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor
growth after re-implantation of primary tumor cells into the secondary
mice
These findings support the use of sulforaphane for chemoprevention of
breast cancer stem cells and warrant further clinical evaluation.
Breast Cencer CAncer stem cells in vitro and in vivo xenograft mouse model
113) Kallifatidis G, Rausch V, Baumann B, et al.
Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut. 2009;58:949–63. [PubMed]
An interesting observation is that sulforaphane was able to inhibit
stem/progenitor cells at the concentrations (0.5~ 5 μM) that hardly
affected the bulk population of cancer cells, implying that sulforaphane
is likely to preferentially target stem/progenitor cells compared to
the differentiated cancer cells.
These results suggest that sulforaphane was able to eliminate breast
CSCs in primary xenografts, thereby abrogating the re-growth of tumors
in secondary mice. Taken together with the in vivo Aldefluor assay
results, these findings suggest that
sulforaphane targets breast CSCs with high potency.
sulforaphane decreased the protein level of β-catenin by up to 85% in
MCF7 and SUM159 cells; and the expression of cyclin D1, one of the
Wnt/β-catenin target genes, declined by up to 77% as well
As a chemoprevention agent, sulforaphane possesses many advantages, such as high bioavailability and low toxicity
A recent pilot study detected an accumulation of sulforaphane in human
breast tissue, with 1.45 ± 1.12 pmol/mg for the right breast and 2.00 ±
1.95 pmol/mg for the left, in eight women who consumed broccoli sprout
preparation containing 200 μmol sulforaphane about 1 hr before the
surgery (36). These concentrations of sulforaphane are expected to be
effective against breast CSCs, based on our in vitro results
114) Li, Y., and T. Zhang. “
Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts.” Future oncology (London, England) 9.8 (2013): 1097-1103.
115) Wu, S., et al. “
Sulforaphane produces antidepressant-and anxiolytic-like effects in adult mice.” Behavioural brain research 301 (2015): 55.
—————————————-
Sulfasalazine – Mantle Cell Lymphoma
116) Bebb, G., et al. “
Sulfasalazine,
inhibits growth of mantle cell lymphoma (MCL) cell cultures via cyst
(e) ine starvation and delays tumour growth in a newly developed murine
MCL model.” BLOOD. Vol. 102. No. 11. 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA: AMER SOC HEMATOLOGY, 2003.
Introduction: Cyst(e)ine deficiency within lymphoid cells leads to a
rapid decline in their levels of glutathione (a major free radical
scavenger), loss of defense against oxidative stress, and subsequently
apoptosis. Lymphoid cells cannot synthesize the amino acid and depend
for growth and viability on its uptake from their micro-environment.
Since lymphomas have been shown to retain the inability to synthesize
cyst(e)ine they are potentially susceptible to cyst(e)ine
starvation-based therapy. We have previously demonstrated that
sulfasalazine (SASP), a drug used for treatment of severe inflammatory
bowel disease and rheumatoid arthritis, is a potent inhibitor of the
cystine/glutamate antiporter, xc-, a major plasma membrane cystine
transporter.
SASP abrogated growth of T and B lymphoma cell
cultures via cystine starvation; SASP, administered intraperitoneally,
markedly inhibited growth of rat Nb2-U17 lymphoma transplants in Nb rats
without major toxicity to the hosts (Anti-Cancer Drugs 14:21, 2003). In the present study we investigated the usefulness of SASP in our newly developed
model of MCL, a B-cell non-Hodgkin lymphoma (NHL), characterized by cyclin D1 and BCL2 over-expression.
Results: Growth of human MCL cultures in Fischer’s medium, supplemented
with 10% fetal bovine serum and antibiotics, was markedly inhibited by
SASP at therapeutic concentrations, showing IC50s of 0.13 and 0.30 for
Z138C and Granta MCL cultures, respectively. Culture growth arrest could
be largely prevented by enhancing cellular cystine uptake using 66 uM
2-mercaptoethanol (reported to promote cystine uptake via the leucine
transporter), indicating that the SASP-induced inhibition resulted from
cyst(e)ine starvation. A study into the efficacy of SASP in vivo was
initiated using SCID/Rag2-M mice injected subcutaneously with Z138C
cells (5 million cells/mouse); such a procedure leads to consistent
development of tumours within 28 days. When tumours had reached a weight
of about 0.1 gr, groups of six mice were treated for 10 consecutive
days with saline (controls) or SASP (250 mg/kg body weight i.p.,
b.i.d.), a dosage well below the maximally tolerated dosage (300 mg/kg
every 8 hr). It was found that treatment with SASP inhibited tumour
growth, showing a delay in growth of at least 7 days, without major
toxicity. Conclusions:
SASP has a marked inhibitory effect on
growth of MCL cell lines in vitro, an effect also seen in vivo in our
murine SC MCL model. SASP may represent a novel approach for
MCL treatment. The precise molecular consequences of SASP treatment on
MCL cells warrant further investigation. Additional studies on the
effect of SASP at higher dosages and in combination with
cyclophosphamide and targeted therapies, eg. ASO and monoclonal
antibodies against bcl-2, are in progress.
Lymphoma
117) Gout, Peter W., Chris R. Simms, and May C. Robertson. “
In vitro studies on the lymphoma growth-inhibitory activity of sulfasalazine.” Anti-cancer drugs 14.1 (2003): 21-29.
Sulfasalazine (SASP) is a novel, potent inhibitor of cellular cystine
uptake mediated by the x(c)- cystine/glutamate antiporter. Lymphoid
cells cannot synthesize cyst(e)ine and depend for growth on its uptake
from their micro-environment. We previously showed that SASP (0.2 mM)
can abrogate lymphoma cell proliferation in vitro by specifically
inhibiting x(c)- -mediated cystine uptake. Intraperitoneal
administration of SASP to Noble rats markedly suppressed Nb2-U17 rat
lymphoma transplant growth, notably without major toxicity to the hosts.
Since Nb2-U17 cells are x(c)- -deficient, the growth arrest was
apparently not due to SASP-tumor cell interaction, but possibly to
interference with x(c)- -mediated cysteine secretion by somatic cells.
In this study we found that replication of x(c)- -deficient Nb2-11
lymphoma cells can be sustained in vitro, in the absence of cystine
uptake enhancers, by co-culturing with IMR-90 fibroblasts known to
secrete cysteine. SASP, at 0.15 and 0.2 mM, arrested replication of
fibroblast-driven Nb2-11 cells by 93 and 100%, respectively, without
impeding fibroblast proliferation. Addition of 2-mercapto-ethanol (60
microM), a cystine uptake enhancer, almost completely prevented this
growth arrest, indicating that SASP specifically inhibited cysteine
secretion by the fibroblasts, a process based on x(c)- -mediated cystine
uptake. It is proposed that the lymphoma growth-inhibitory activity of
SASP in vivo involves inhibition of cysteine secretion by
tumor-associated somatic cells (macrophages, dendritic cells), leading
to cysteine starvation of the tumor cells and apoptosis. The difference
between the lymphoma cells and fibroblasts in sensitivity to SASP
treatment is consistent with the marked antitumor effect of SASP lacking
significant side effects.
Small cell Lung cancer full pdf
118) Guan, Jun, et al. “The x c− cystine/glutamate antiporter as a
potential therapeutic target for small-cell lung cancer: use of
sulfasalazine.” Cancer chemotherapy and pharmacology 64.3 (2009):
463-472.
Conclusions The xc- cystine/glutamate antiporter is
potentially useful as a target for therapy of SCLC based on
glutathione depletion. Sulfasalazine may be readily used
for this approach, especially in combination chemotherapy.
pancreatic full pdf
119) Lo, M., et al. “Potential use of the anti-inflammatory drug,
sulfasalazine, for targeted therapy of pancreatic cancer.” Current
Oncology 17.3 (2010): 9-16.
Breast
120) Narang, Vishal S., et al. “Suppression of cystine uptake by
sulfasalazine inhibits proliferation of human mammary carcinoma cells.”
Anticancer research 23.6C (2002): 4571-4579.
Prostate
121) Doxsee, Daniel W., et al. “Sulfasalazine‐induced cystine
starvation: Potential use for prostate cancer therapy.” The Prostate
67.2 (2007): 162-171.
————————–
Butyrate
2016
122) Zhang, J., et al. “
Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis.” PloS one 11.1 (2016): e0147218.
2007
123) Pajak, B., A. Orzechowski, and B. Gajkowska. “
Molecular basis of sodium butyrate-dependent proapoptotic activity in cancer cells.” Advances in Medical Sciences (De Gruyter Open) 52 (2007).
This review outlines the molecular events that accompany the antitumor
action of sodium butyrate (NaBt). Butyrate, alow-molecular weight
four-carbon chain volatile fatty acid
(VFA) has been previously shown to withdraw cells from cell cycle or to
promote cell differentiation, and finally to induce programmed cell
death. Recent advances in molecular biology indicate, that
this product of large bowel microbial fermentation of dietary fiber, might evoke the above-mentioned effects by indirect action on genes. NaBt was shown to
inhibit histone deacetylase activity, allowing DNA binding of several transcription factors. Higher genomic activity leads to the higher expression of
proapoptotic genes,
higher level of their protein products and elevated sensitivity to
death ligand-induced apoptosis. Cancer cells might be arrested in G1
phase of cell cycle in a p21-dependent manner. Proapoptotic activity of
NaBt includes higher expression of membrane death receptors (DR4/5),
higher level and activation of Smad3 protein in TGF-beta-dependent
apoptotic pathway, lower level of antiapoptotic proteins (cFLIP, XIAP)
and activation of proapoptotic tBid protein. Thus, both intrinsic and
extrinsic apoptotic pathways are stimulated to ampify the apoptotic
signals. These effects are specific for tumor but not for regular cells.
Unique properties of NaBt make this agent a promising metabolic
inhibitor to retard tumorigenesis to suppress tumor growth.
full pdf
Inhibits Telormerase Activity
124) Choi, Yung Hyun. “Apoptosis of U937 human leukemic cells by
sodium butyrate is associated with inhibition of telomerase activity.”
International journal of oncology 29.5 (2006): 1207-1213.
Sodium butyrate as a histone deacetylase inhibitor. Exposure of U937 cells to sodium butyrate resulted in growth inhibition and induction of apoptosis in a dose-dependent manner.
The increase in apoptosis was associated with the up-regulation in
pro-apoptotic Bax expression, and down-regulation of anti-apoptotic
Bcl-2 and Bcl-XL.
sodium butyrate markedly inhibited the activity of telomerase and the
expression of human telomerase reverse transcriptase (hTERT), a main
determinant of the telomerase enzymatic activity, was progressively
downregulated by sodium butyrate.
In addition to the deregulation of apoptosis, it is increasingly
clear that the process of neoplasia is characterized by the activation
of telomerase that adds telomeric repeats to the ends of replicating
chromosomes, telomeres
Critically short telomeres are suggested to cause irreversible cell growth arrest and cellular senescence.
telomerase reactivation is a rate-limiting step in cellular
immortality and carcinogenesis, and telomerase repression can act as a
tumor-suppressive mechanism.
Sodium butyrate is a short chain fatty acid normally produced as a
result of bacterial fermentation of fiber in mammalian intestines,
representing one of the end products of carbohydrate breakdown
the ratio between the level of proapoptotic Bax and that of the
anti-apoptotic factor Bcl-2 determines whether a cell responds to an
apoptotic signal.
there was a concentration-dependent down-regulation of Bcl-2 members
such as Bcl-2 and Bcl-XL in sodium butyrate-treated U937 cells, but the
levels of Bax were up-regulated, resulting in an increase in the ratio
of
Bax/Bcl-2 and/or Bcl-XL.
In conclusion, our results indicated that
sodium butyrate
potently suppresses the proliferation of U937 human leukemic cells by
inducting apoptosis through an increase of Bax expression and activation
of caspase-3. The growth inhibitory effects of sodium butyrate were
also associated with a specific inhibition of hTERT expression and telomerase activity.
Lauric Acid – coconut oil
2013 full pdf
125) Fauser, J. K., et al. “Induction of apoptosis by the medium-chain length fatty acid
lauric acid in colon cancer cells due to induction of oxidative stress.” Chemotherapy 59.3 (2013): 214-224.
Lauric acid, as a component of triglycerides, comprises about half of the fatty acid content in
coconut milk, coconut oil,
laurel oil, and palm kernel oil. Compared to butyrate, lauric acid
displayed preferential antineoplastic properties, including induction of
apoptosis in a CRC cell line.
The SCFA butyrate has demonstrated the capacity to induce apoptosis by:
inhibiting
histone deacetylase activity, inducing cell cycle arrest, promoting
differentiation, activating NF-κB, downregulating α 2 β 1 , modifying
glucose availability, and inducing caspase activation in CRC cell lines [1, 2, 9–12] .
126) Jurečeková, Jana, et al. “Targeting of Bcl-2 family proteins for
treatment of acute leukaemia.” General physiology and biophysics 30
(2011): S3-S12.
127) Fauser, Jane Kathryn. Medium Chain Fatty Acids and Wnt/β-Catenin
Inhibitors as Adjunctive Colorectal Cancer Chemotherapeutic Agents.
Diss. The University of Adelaide, 2012.
128) Nohara, Kazunari, Yoshiko Yokoyama, and Kazutaka Kano. “The
Important Role of Caspase-10 in Sodium Butyrate.” Kobe J. Med. Sci 53.5
(2007): 265-273.
————————————-
Ivermectin
2015
129 ) Draganov, Dobrin, et al. “
Modulation
of P2X4/P2X7/pannexin-1 sensitivity to extracellular ATP via ivermectin
induces a non-apoptotic and inflammatory form of cancer cell death.” Scientific reports 5 (2015).
We found that Ivermectin kills mouse and human triple-negative breast
cancer (TNBC) cells through augmented P2X7-dependent purinergic
signaling associated with caspase-1 and caspase-3 activation.
FIg 7 Model of P2X4/P2X7/Pannexin-1-induced cancer cell death.
Ivermectin induces P2X4/P2X7-dependent activation of Pannexin-1 channels
and release of ATP. The release of ATP might be transiently protective,
but only in cell types that are highly sensitive to Ivermectin-induces
cell swelling when ATP and Ca2+ signaling are essential for control of
cell volume. In cancer cells where no cell size changes can be observed
(for example human TNBC MDA-MB-231 cells), high concentrations of ATP
(1–3 mM) immediately enhance Ivermectin cytotoxicity. Potentiated P2X7
receptor signaling drives a fast progressing necrotic/pyroptotic
mechanism driven by NADPH oxidases-generated ROS, cytosolic Ca2+/CaMKII
activation, and MPTP, and characterized by caspase-1 cleavage, due to
possible NLRP3 inflammasome activation. Necrotic killing is followed by a
slower progressing apoptotic cell death program mediated by caspase-3
activation. The failure of the default apoptotic pathway might be
attributed to faster activation of caspase-1, inadequate autophagic
control of mitochondrial MPTP, collapse of cellular energy metabolism,
resulting in rapid progression of necrotic cell death. Damage to
mitochondria and ER stress as well as potential depletion of cellular
ATP reserves simultaneously promote autophagy that might render even the
slower apoptotic pathway immunogenic.
2014 full free
130) Melotti, Alice, et al. “
The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT‐TCF pathway responses in human cancer.” EMBO molecular medicine (2014): e201404084.
as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.
We find that macrocyclic lactones of the Avermectin family have
specific anti-WNT-TCF response activity in human cancer cells and that
the clinically approved compound Ivermectin (EMEA- and FDA-approved) is a
specific WNT-TCF response blocker at low micromolar concentrations.
cancer stem cells
Pre-treatment with Ivermectin and Selamectin inhibits colon cancer stem cell self-renewal in clonogenic spheroid assays
These results suggest an action on both the bulk of the tumor and its cancer stem cells.
Moreover, they might also be useful as routine prophylactic agents,
for instance against nascent TCF-dependent intestinal tumors in patients
with familial polyposis and against nascent sporadic colon tumors in
the general aging population.
—————————————————————-
131) O’neill, Paul M., Victoria E. Barton, and Stephen A. Ward. “The
molecular mechanism of action of artemisinin—the debate continues.”
Molecules 15.3 (2010): 1705-1721.
Molecular Mechanism of Action of Artemisinine Debate ONeill 2010
132)
Robert, Anne, Jérôme Cazelles, and Bernard Meunier. “Characterization of the alkylation product of heme by the antimalarial drug artemisinin.” Angewandte Chemie International Edition 40.10 (2001): 1954-1957.
133) full free pdf
Mathur, Rohit, et al. “Targeting Wnt pathway in mantle cell
lymphoma-initiating cells.” Journal of hematology & oncology 8.1
(2015): 63.
Targeting Wnt pathway in mantle cell lymphoma initiating cells Mathur 2015
134) Li, Yanyan, et al. “
Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.” The Journal of nutritional biochemistry 22.9 (2011): 799-806.
135) Rodova, Mariana, et al. “
Sonic
hedgehog signaling inhibition provides opportunities for targeted
therapy by sulforaphane in regulating pancreatic cancer stem cell
self-renewal.” PloS one 7.9 (2012): e46083.
Given the requirement for Hedgehog in pancreatic cancer, we
investigated whether hedgehog blockade by SFN could target the stem cell
population in pancreatic cancer. In an in vitro model, human pancreatic
CSCs derived spheres were significantly inhibited on treatment with
SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN
inhibited the components of Shh pathway and Gli transcriptional
activity. Interference of Shh-Gli signaling significantly blocked
SFN-induced inhibitory effects demonstrating the requirement of an
active pathway for the growth of pancreatic CSCs. SFN also inhibited
downstream targets of Gli transcription by suppressing the expression of
pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα
and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2
and activation of caspases. Our data reveal the essential role of
Shh-Gli signaling in controlling the characteristics of pancreatic CSCs.
We propose that pancreatic cancer preventative effects of SFN may
result from inhibition of the Shh pathway. Thus Sulforaphane potentially
represents an inexpensive, safe and effective alternative for the
management of pancreatic cancer.
HDAC Inhibitors in Mantel Cell
136) Heider, Ulrike, et al. “Histone deacetylase inhibitors reduce
VEGF production and induce growth suppression and apoptosis in human
mantle cell lymphoma.” European journal of haematology 76.1 (2006):
42-50.
Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors
sodium butyrate (NaB) and suberoylanilide hydroxamic acid vorinostat (SAHA) for 8-72 h.
Mantle cell lymphoma (MCL) is an incurable disease with an aggressive
course and novel treatment strategies are urgently needed. The purpose
of this study was to evaluate the effects of histone deacetylase (HDAC)
inhibitors, a new group of antiproliferative agents, on human MCL cells.
METHODS: Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were
exposed to different concentrations of the HDAC inhibitors sodium
butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h.
Their effects on cell viability, apoptosis induction and cell cycle
proliferation were studied. Moreover, the influence of SAHA on the
expression of cyclin D1, the cell cycle regulators p21 and p27 and the
production of vascular endothelial growth factor (VEGF) were analyzed.
RESULTS: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells.
MTT
assays and Annexin-V staining showed that they potently inhibited
viability in a dose-dependent manner and induced apoptosis in all cell
lines tested. Cell cycle analysis indicated that their exposure to SAHA
or NaB decreased the proportion of cells in S phase and increased the
proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the
two HDAC inhibitors resulted in downregulation of cyclin D1.
SAHA lead to an upregulation of p21 in all cell lines and an
upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of
p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production
of the angiogenic cytokine VEGF. Treatment with NaB increased the
expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells
no effect was noted. The expression of p27 remained constant in all
three cell lines after exposure to NaB.
CONCLUSION: Based on these findings, we provide evidence that HDAC
inhibitors have antiproliferative effects in MCL and may represent a
promising therapeutic approach.
137)
Ivermectin pharmacology and therapeutic applications Sunita Chhaiya 2012 Chhaiya,
Sunita B., et al. “IJBCP International Journal of Basic & Clinical
Pharmacology.” International Journal 2.6 (2013): 799. Ivermectin
pharmacology and therapeutic applications Sunita Chhaiya 2012
Pediculosis head lice dosage- Two 200 mcg/kg tablets a week apart. (12 mg tablet for a 60 kg male).
138)
NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011 NEW ZEALAND DATA SHEET STROMECTOL ivermectin 3 mg tablet 2011
Berberine – Berberine inhibits WNT Pathways
139) Biofactors. 2013 Nov-Dec;39(6):652-62.
Berberine acts as a natural inhibitor of Wnt/β-catenin signaling–identification of more active 13-arylalkyl derivatives. Albring KF1, Weidemüller J, Mittag S, Weiske J, Friedrich K, Geroni MC, Lombardi P, Huber O.
Aberrant activation of the canonical Wnt/β-catenin signaling pathway has been reported for numerous tumors of different origins.
In most cases, mutations in components of the Wnt signaling pathway or
in β-catenin itself were detected which ultimately induce a genetic
program that promotes cell proliferation and attenuates apoptosis.
Thus, targeting of Wnt/β-catenin signaling is of specific therapeutic
interest. As a result of berberine treatment, cellular levels of active
β-catenin were reduced concomitant with an increase in the expression
of E-cadherin.
140) Eur J Pharmacol. 2014 Oct 5;740:584-95.
Targets and mechanisms of berberine, a natural drug with potential to treat cancer with special focus on breast cancer.Jabbarzadeh Kaboli P1, Rahmat A2, Ismail P3, Ling KH4.
Berberine was shown to be effective in inhibiting cell proliferation
and promoting apoptosis invarious cancerous cells. Some signaling
pathways affected by berberine, including the MAP (mitogen-activated
protein) kinase and Wnt/β-catenin pathways, are critical for reducing
cellular migration and sensitivity to various growth factors.
Epiphany Against cancer
full free pdf
141) Guamán Ortiz, Luis Miguel, et al. “Berberine, an epiphany against cancer.” Molecules 19.8 (2014): 12349-12367.
BBR treatment promotes cell cycle arrest and death in human cancer
cell lines, coupled to an increased expression of apoptotic factors
BBR functions as an inhibitor of the telomere elongation by blocking
the telomerase activity through formation of a G-quadruplex with
telomeric DNA
BBR has the potential to modulate and regulate Wnt/β-catenin pathway
[56], which in normal cells is inactivated by ubiquitination and
subsequent degradation of the β-catenin protein,
BBR was proved to alter the mitochondrial membrane potential
(MMP), inhibit mitochondrial respiration leading to mitochondrial
dysfunction and regulate the expression of Bcl-2 family members, as
Mcl-1 [45,47]. Alterations in mitochondrial membrane stimulate the
release of cytochrome c promoting the formation of reactive oxygen
species (ROS) that trigger apoptosis that requires the activation of
caspases and poly(ADP-ribose) polymerase-1 (PARP-1)
cleavage
Silibinin – Inhibits WNT pathway
full free pdf
142) Tiwari, Prabha, and K. P. Mishra. “Silibinin in cancer therapy: A
promising prospect.” Cancer Research Frontiers 1.3 (2015): 303-318.
Silibinin also
inhibited Wnt/β-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human breast cancer cells MDA-MB-231 and T-47D
Exogenous SOD markedly enhanced silibinin-induced apoptosis
clinical trials for the treatment of hepatotoxicity in childhood
acute lymphoblastic leukemia (ALL). Silymarin (The target dose of
silibinin was 5.1 mg/kg/day) was administered orally for 28 days and it
significantally reduced liver toxicity in children with ALL (74).
Recently a new silibinin drug formulation Legasil® administration
improved hepatic failure due to extensive liver infiltration in a breast
cancer patient (75).
A Phase II Study to Assess Efficacy of Combined Treatment with Erlotinib (Tarceva) and Silybin-phytosome (
Siliphos) in Patients with EGFR mutant lung adenocarcinoma is going on (ClinicalTrials.gov Identifier:
Silibinin has also shown promising results against cancer stem cells, supporting further development of anti-cancer therapeutics that target tumor stem cells.
143) Siegel, Abby B., et al. “A phase I dose-finding study of silybin
phosphatidylcholine (milk thistle) in patients with advanced
hepatocellular carcinoma.” Integrative cancer therapies (2013):
1534735413490798.
Targeting Cancer Stem Cells – Pterostilbene
144) Wu, Chi-Hao, et al. “T
argeting cancer stem cells in breast cancer: potential anticancer properties of 6-shogaol and pterostilbene.” Journal of agricultural and food chemistry 63.9 (2015): 2432-2441.
Breast cancer stem cells (BCSCs) constitute a small fraction of the
primary tumor that can self-renew and become a drug-resistant cell
population, thus limiting the treatment effects of chemotherapeutic
drugs. The present study evaluated the cytotoxic effects of five
phytochemicals including 6-gingerol (6-G), 6-shogaol (6-S),
5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-HF), nobiletin (NOL), and
pterostilbene (PTE) on MCF-7 breast cancer cells and BCSCs. The results showed that 6-G, 6-S, and
PTE
selectively killed BCSCs and had high sensitivity for BCSCs isolated
from MCF-7 cells that expressed the surface antigen CD44(+)/CD24(-).
6-S and PTE induced cell necrosis phenomena such as membrane injury and
bleb formation in BCSCs and inhibited mammosphere formation. In
addition, 6-S and PTE increased the sensitivity of isolated BCSCs to
chemotherapeutic drugs and significantly increased the anticancer
activity of paclitaxel. Analysis of the underlying mechanism showed that
6-S and PTE decreased the expression of the surface antigen CD44 on
BCSCs and promoted
β-catenin phosphorylation through the
inhibition of hedgehog/Akt/GSK3β signaling, thus decreasing the protein
expression of downstream c-Myc and cyclin D1 and reducing BCSC stemness.
human lung adenocarcinoma
145) Yang, Yang, et al. “
Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells.” PloS one 8.5 (2013): e62652.
antitumor activity of PTE against human lung adenocarcinoma in vitro
and in vivo and explored the role of the Notch1 signaling pathway
PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells.
reduced mitochondrial membrane potential (MMP) and a decreased
intracellular glutathione content but also by increases in the apoptotic
index and the level of reactive oxygen species (ROS).
Activation of the Notch1 Intracellular Domain (NICD) protein and
activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA
prevented the induction of NICD and Hes1 activation by PTE treatment and
sensitized the cells to PTE treatment.
Down-regulation of Notch signaling also prevented the activation of
pro-survival pathways (most notably the PI3K/Akt pathway) after PTE
treatment.
Chloroquin and Pterostilbene – autophagy inhibitor potentiated pterostilbene effect
146) Papandreou, Ioanna, et al. “
Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.” Experimental cell research 339.1 (2015): 147-153.
We performed a screen of 1726 small, drug like molecules to identify
those that could activate an ER-stress responsive luciferase gene. After
secondary screening, we determined that the
plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group.
ER stress can be particularly toxic to cells with high ER load, so we
examined their effect on cells expressing the Wnt family of secreted
glycoprotein growth factors. Molecular analysis determined that these
ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16.
Combining
pterostilbene (to induce ER stress) with chloroquine (to inhibit
autophagy) lead to significant cellular toxicity in cells from
aggressive acute lymphoblastic leukemia.
CONCLUSIONS: Plant stilbenes are potent inducers of ER stress. However,
their toxicity is more pronounced in cancer cells expressing Wnt growth
factors.
The toxicity of stilbenes in these ALL cells can be
potentiated by the addition of autophagy inhibitors, suggesting a
possible therapeutic application.
147)
vorinostat HDAC Inhibitors
Sakajiri, Sakura, et al. “
Histone deacetylase inhibitors profoundly decrease proliferation of human lymphoid cancer cell lines.” Experimental hematology 33.1 (2005): 53-61.
Methylation of tumor suppressor genes is frequently observed in human
cancers. These genes are silenced by histone deacetylase (HDAC)
recruited by methylated DNA in their promoter regions. HDAC removes
acetyl groups from histones and prevents the basic transcriptional
machinary access to the target gene, leading to transcriptional
repression. HDAC inhibitors (HDACIs) can restore the expression of the
tumor suppressor and/or cell cycle regulatory genes in cancer cells and
block the cellular proliferation of these cells. In this study, we
investigated the in vitro antiproliferative activities of the HDACIs,
suberoylanilide hydroxamic acid (SAHA), and valproic acid against 14
human lymphoid cancer cell lines. All of these cell lines were sensitive
to the antiproliferative effects of the HDACI. SAHA induced either G1
or G2-M arrest as well as apoptosis. SAHA downregulated cyclin D1 and
D2, and upregulated p53, p21, and p27. Chromatin immunoprecipitation
analysis revealed a remarkable increase in the level of acetylated
histones associated with the p21 promoter after SAHA treatment. In nude
mice, SAHA significantly inhibited growth of a mantle cell lymphoma
without major toxic side effects. In summary, HDACIs are promising
therapeutic agents for human lymphoid cancers.
——————-
HerbalZym
148)
Modulation
of β-catenin signaling by natural agents induces apoptotic cell death
in many common cancers, including colon cancer, breast cancer and
prostate cancer. Part 1
149)
PART TWO
Berberine reduces cellular levels of active β-catenin and inhibits β-catenin transcriptional activity.
Silymarin,
honokiol, lupeol, genistein, gugulipid, resveratrol, quercetin, EGCG,
lycopene, sulforaphane, ellagic acid, Vitamin D, and
omega-3-polyunsaturated fatty acids also antagonize or modulate
Wnt/β-catenin signaling. We believe that these natural agents
that are non-toxic in nature could be used either alone or in
combination with conventional therapeutics for the prevention and/or
treatment of a variety of cancers.
Parthenolide
150) Bioavailable Parthenolide Histone Deacetylase (HDAC) Inhibitor, Part 1
151)
Bioavailable Parthenolide Histone Deacetylase (HDAC) Inhibitor, Part 2
link to this page:
http://wp.me/p3gFbV-3nF
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
http://www.drdach.com
http://www.naturalmedicine101.com
http://www.bioidenticalhormones101.com
http://www.truemedmd.com
Disclaimer click here:
http://www.drdach.com/wst_page20.html
The
reader is advised to discuss the comments on these pages with his/her
personal physicians and to only act upon the advice of his/her personal
physician. Also note that concerning an answer which appears as an
electronically posted question, I am NOT creating a physician — patient
relationship. Although identities will remain confidential as much as
possible, as I can not control the media, I can not take responsibility
for any breaches of confidentiality that may occur.
Copyright (c) 2016 Jeffrey Dach MD All Rights Reserved. This article
may be reproduced on the internet without permission, provided there is a
link to this page and proper credit is given.
FAIR USE NOTICE: This site contains copyrighted material the use of
which has not always been specifically authorized by the copyright
owner. We are making such material available in our efforts to advance
understanding of issues of significance. We believe this constitutes a
‘fair use’ of any such copyrighted material as provided for in section
107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section
107, the material on this site is distributed without profit to those
who have expressed a prior interest in receiving the included
information for research and educational purposes.
Serving Areas of: Hollywood, Aventura, Miami, Fort Lauderdale,
Pembroke Pines, Miramar, Davie, Coral Springs, Cooper City, Sunshine
Ranches, Hallandale, Surfside, Miami Beach, Sunny Isles, Normandy Isles,
Coral Gables, Hialeah, Golden Beach ,Kendall,sunrise, coral springs,
parkland,pompano, boca raton, palm beach, weston, dania beach, tamarac,
oakland park, boynton beach, delray,lake worth,wellington,plantation.
Mary
is a 57 year old female with chronic fatigue, dry, brittle hair, dry
skin, muscle aches and pains, and depression, all obvious symptoms of a
low thyroid condition. Mary has been to a number of endocrinologists,
primary care doctors and even sought advice from her hair stylist. Her
latest doctor prescribed a thyroid pill called Levothyroxine (50 mcg)
which has done little to relieve her symptoms. In addition, she has
depression, and her psychiatrist prescribed an SSRI antidepressant,
called Zoloft. She also takes Xanax for bouts of anxiety and insomnia.
Mary came into the office frustrated with her conventional medical
treatment which was not helping her.
Mary
was switched from Levothyroxine to Naturethroid from RLC labs and
within a week reported improvement in clinical symptoms. Six weeks later
Mary’s Naturethroid dosage was gradually increased to Two and a Half
Tablets every day (Using one grain tablets of 65 mg each) . Mary reports
improvement. She has tapered off her antidepressants, as she no longer
needs them.
In our office we use Nature-throid from RLC labs.
(Disclosure: NONE, I have no financial relationship with RLC labs, the
manufacturer of Nature-Throid NDT – natural dessicated thyroid pills) .
Japan in Agreement
The answer is obvious. Follow the money trail. Synthroid is the fourth most prescribed drug in America with 70 million prescriptions. Abbot labs, the makers of Synthroid, uses the massive profits to finance and fund Endocrinology Groups and Societies, their meetings, and clinical research grants. They also fund the key opinion leaders
to give lectures at meetings in support of Synthroid and the TSH test.
This is all done in spite of the obvious clinical inferiority of T4 only
medications such as levothyroxine, and the unreliability of the TSH
test to monitor adequacy of treatment. For many decades now, mainstream
endocrinology has been completely corrupted by huge cash infusions from
Big Pharma. Welcome to America. It’s a great country.
