Artesunate I.V. For Injection

Jeffrey Dach MD
Bioidentical Hormones Natural Thyroid

Artemisinin our Ultimate Cancer Weapon a Gift from China
Tu You You Artemesinin_China_Daily2

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 Xray of the colon. Susan was sent to a colon cancer surgeon who told her she needed an operation to remove the cancer from her colon. Left image: Tu You You winner of 2015 Nobel Prize in Medicine Courtesy of China Daily News. This article is part one, for part two click here.

Artemisinin Prospective Randomized Trial in Colon Cancer

Apple_Core_Colon_Cancer_Barium_Enema_artemesininSusan read in the newspaper about Dorothy Bradshaw, a colon cancer patient who participated in a clinical study with Dr. Sanjeev Krishna at St George University London in 2010.(71)

Dorothy took a new anti-cancer drug called Artesunate (an artemisinin derivative) for two weeks before her colon resection to remove the tumor. Five years later, she is alive and well. This randomized study was done with 20 colon cancer patients awaiting surgery. Half received the Artesunate pill for two weeks prior to surgery, and the other half a placebo. Five years later, there were 6 cancer recurrences in the placebo group, but only one in the Artesunate (Artemisinin) group. There were no deaths in the Artesenate group, compared to three deaths in the placebo group.(70-71) I was very impressed by this.

Susan called me to ask if Artemisinin could improve her chances of beating cancer recurrence after surgery. I said to Susan, “Artemisinin is our ultimate weapon against cancer, a gift from China”

Left Image Artemisinartemesinin chemical structure_2in chemical structure. Active portion of molecule is the endo-peroxide bridge (red arrows) highly reactive oxygen bridge which reacts with the iron in malaria organisms, and the iron in cancer cells.

Ridiculing Chinese Herbs

Back in the old days when I was hospital based physician, we took lunch in the doctor’s dining room where conversation included amazement and ridicule at the stories of patients who took Chinese herbs for their medical condition. The surgeons had a good laugh, expressing amazement that any intelligent American would choose to take a Chinese herb for a medical condition. Below image: Dr. Tu YouYou wins Nobel prize in Medicine 2015 for discovery of Artemisinin. Image Courtesy of IFLScience and China’s Daily .

Artemisinin – A Gift From The Chinese GovernmentTu You You Artemesinin_China_Daily_2015_Nobel _PrizeBack in the 1960’s during the Vietnam War, the North Vietnamese soldiers succumbed to malaria in great numbers. This military issue prompted the Chinese government to develop better and more effective anti-malarial drugs. China enlisted the help of a young medical student named, Dr Tu YouYou who began working. She uncovered an ancient Chinese medical text in an archaeological excavation written by Ge Hong (281–340 AC), which describes an herbal tea, sweet wormwood, to treat fevers and chills. This sweet wormwood tea was later mentioned in the 1596 Chinese Compendium by Li Shizen. Dr Tu Youyou ultimately isolated the active molecule in the tea, called artemisinin (figure 1 above), an effective anti-malaria drug, for which she received the 2015 Nobel prize in Medicine. Artemisinin and derivatives like artesunate are now life saving malaria drugs used by millions. Who’s laughing at Chinese Herbs Now?

Antimalarial Drugs are Also Anti-Cancer Drugs

artemesinin_reacting_with_HemeLeft Upper Image: Artemisinin reacting with Heme courtesy of O’neill, et al Molecular Mechanism of Action of Artemisinine Debate ONeill 2010. (131)

Dr. Das reports in a 2015 article that Artemisinin (or derivatives) are effective against 55 cancer cell lines with inhibitory effects against pancreatic cancer, osteosarcoma, lung cancer, colon, melanoma, breast, ovarian, prostate, central nervous system, lymphoma, leukemia and renal cancer cells. (1)

The molecular mechanism by which artemisinin compounds serve as effective anti-cancer agents can be found in its molecular structure, the endo-peroxide bridge which reacts with the iron molecule. (see figure 1 above)

Cancer Cells Contain Massive Amounts of Iron (Fe)

We can exploit key metabolic differences between cancer cells and normal cells, to come up with ways to kill cancer cells, while leaving normal cells unharmed as discussed in a previous article, cancer as a metabolic disease. This is the targeted non-toxic approach to cancer treatment. One such key metabolic difference is the higher Iron (Fe) content of cancer cells.

Heme_Artemesinin_alkylation_fenton_ironLeft Image shows endo-peroxide bridge (oxygen) in Artemisinin (1) attaching to Heme iron (Fe) (2) courtesy of Robert et al, “Characterization of the alkylation product of heme by the antimalarial drug artemisinin.” (132)

Cancer Cells Contain Massive Amounts of Iron in Lysosomes

Cancer cells express high levels of the transferrin receptors for internalizing iron (Fe) at a tremendous rate.(21) This is a useful difference from normal cells. The cancer cells have a voracious appetite for Iron, and contain massive quantities of iron compared to normal cells. In addition, the transport mechanism for iron in cancer cells, called transferrin receptors are massively up-regulated.(18) In fact, a correlation between expression of transferrin membrane receptor and Ki-67 (a marker of tumor proliferation) has also been reported,(19) The more aggressive the tumor, the greater number of transferring receptors. This difference in iron content and iron transport is why artemisinin compounds kill cancer cells selectively while sparing normal cells.

Heme_Porphyrin_RingAddition of Iron Enhances Killing Effect of Artemisinin

Left image: Schematic of Hemoglobin Molecule with Central Fe (Red). This Fe is Iron in the center of Heme Molecule .Courtesy of wikimedia.

Since the anti-cancer effect of artemisinin relies on presence of Iron in the cancer cell, its effects are up-regulated 1.5-10 fold by ingestion of iron supplements, as you might expect.(20)

There is also synergy of ART with ALA (Amino Levulinic Acid, the precursor molecule for heme synthesis). However, considering the high cost of GleoLan ($4,000) per vial), perhaps ingestion of liquid chlorophyll would provide similar precursors and increase heme synthesis at lower cost.(152-155) See: Xu, X. F., et al. “Effects of sodium ferrous chlorophyll treatment on anemia of hemodialysis patients and relevant biochemical parameters.” Journal of biological regulators and homeostatic agents 30.1 (2016): 135-140.

Fenton Reaction in Lysosomes – Ferroptosis

What are lysosomes? Lysosomes are the cell organelles which contain acid used for digestion and degradation of unwanted intracellular debris and endocytosed bacteria and proteins. For example, our white cells, called neutrophils, kill bacteria in our blood stream by eating them. Once eaten, these unwanted proteins are digested in lysosomes, The acid in the lysosome is produced by a molecular machine called the “V-ATPase”, a molecular pump for acid production. Lysosomes often accumulate large amounts of iron, especially in cancer cells, which may then react with oxygen, called Fenton reaction, causing release of hydroxyl radicals. This compromises the lysosomal membrane with release of acid contents freely into the cell cytosol initiating a form of cell death is called “ferroptosis” (53) (as opposed to apoptosis), as we will detail below. (5) In this scenario, Artemisinin enters the cancer cell lysosomes, which already contain iron as a degradation product from ferritin. The endoperoxide oxygen bridge in artemisinin reacts with iron , the Fenton Reaction, and hydroxyl radicals are produced. The diagram below illustrates the mode of action of Artemisinin in the cancer cell.

Mode of Action of Artemisinin Cancer Cell Death from Yang et al.(6)

Artesunate induces cell death in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin YANG 2014 Fig F9BFigure 9E from Yang et al. Artemisinin enters cancer cell along with iron loaded ferritin. Both enter the lysosome which then triggers mitochondria reactive oxygen species (ROS) and caspase 3 programmed cell death.(6)

Cancer Cell Killing Mechanism according to Yang et al:

Firstly Artemisinin (ART) accumulates in the lysosomes. Second, ART increases lysosomal acidification, cathepsin enzyme activity, and protein degradation via promoting lysosomal V-ATPase assembly. ART induces autophagy, based on the observations that ART increased autophagosomes formation and enhanced autophagic flux.

“We believe that this perinuclear clustering of lysosomes is, in fact, an indication of autophagy induction. We observed increase of mitochondrial ROS implicating lysosomal iron as a critical mediator in ART-induced mitochondrial ROS production and cell death. It is possible that enhanced lysosomal degradation of ferritin induced by ART leads to the transient increase of cytosolic ferrous iron, which then affects the mitochondria, leading to enhanced mitochondrial ROS production.”(6)

BAF (bafilomycin A1), a lysosomal (V)-ATPase inhibitor, was able to effectively inhibit the cell death induced by ART . “Ferritin delivery and degradation in lysosomes is required for the toxicity of ART. Therefore, lysosomal inhibitors significantly protect the cells from ART-induced cell death via blockage of ferritin degradation.”(6)

Chloroquin inhibits Ferritin Degradation and Cell Death induced by ART

“In fact, we also found that chloroquine inhibited the ferritin degradation and cell death induced by ART as efficiently as BAF (data not shown).”

BAF is a lysosomal inhibitor which prevents artemisinin cell death. DFO is iron chelator which inhibits cell death. NAC (N acetyl cysteine inhibits ROS )inhibits cell death. Images courtesy of Yang, Nai-Di, et al. (6) “Artesunate induces cell death in human cancer cells “

Lysosomal Clustering and Accumulation At Nucleus

When Artemisinin enters the cancer cell, it causes a peculiar re-arrangement of the lysosomes and mitochondria in a pattern typical for autophagy (the cell eats itself and dies) as reported by Dr Brady (see below). This peri-nuclear clumping has also been observed in experiments which knock out KIF5B, the only microtubule motor protein associated with the lysosomes. Therefore it has been speculated that the effect of Artemisinin in the lysosome is to impair the microtube motor proteins. This perinuclear clustering of organelles is a prelude to programmed cell death.

Left image: Top Row areArtemesinin_perinuclear clusterine_auto_phago_lysosomes_2Untreated Breast Cancer Cells showing lysosomes (dark stained particles) dispersed throughout cells.

Bottom Row, Breast cancer cells treated with Artemisinin. Yellow arrows point to peri-nucelar clustering of autophagosomes (lysosomes).

Images from Figure 3 courtesy of Hamacher-Brady, Anne, et al.(80) “Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production.” J. Biol. Chem 2011.286 (2010): 6587-6601.

Artemesinin_Breast_Cancer_Study_24Left Image shows Breast Cancer Cells (Top row, yellow arrow) treated with artemisinin and holotransferrin demonstrating clustering of mitochondria (green) and lysosomes(red). Normal breast cells (lower row) show no clustering effects. Images from Figure 9 courtesy of Hamacher-Brady, Anne, et al.(80)

Dr Kundu reports in a 2015 article in Acta tropica that many anti-malarial drugs serve as anti-cancer drugs and vice versa (22). Curcumin, resveratrol, pterostilbene, allicin (from garlic) are among the many natural substances that work together in synergy with Artemisinin. In addition, Artimisisin, and derivatives, enhance the anti-cancer activity of most conventional chemotherapy agents.(22)

Artemisinin Derivatives and Ferritin Tagging

Efficacy of Artimisinin may be impaired by poor absorption and relatively low blood level. How can the potency and efficacy of Artemisinin be increased ? Make a derivative such a artemether, artesenuate. Derivatives are modified artemisinin compounds possessing greater bio-availability and potency. Be careful here because greater bio-availablity and potency may be associated with increased toxicity which we will discuss below.

Transferrin Tagged Artemisinin

Another technique is to tag the Artemisin molecule with transferrin, the Iron carrier protein. This combination had greater anti-cancer potency see Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Nakase. (83)

Other Anti-Cancer Treatments Work in Synergy

Firstly, intra-cellular iron is required for Artemisinin to kill the cancer cell. Having the patient take an Iron supplement (such as Iron bis-glycinate, Optferrin Pure Encapsulations) increases the effect of the Artemisinin. However one 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 are synergistic with artemisinin. These include Vitamin D, Iodine (iodoral) Berberine, Curcumin (lipospheric) (24-29), Resveratrol, Pterostilbene, Allicin, Melatonin, Sulphoraphane, Butyrate, and high dose IV Vitamin C (79), fresh juicing with organic carrots and organic beets, Lipo-Colostrum (Soveriegn Labs), a good multivitamin (One Multi Pure Encapsulation) . (79)

Eureka ! High Dose IV Vitamin C Synergy with Artemisinin (79)

The suppressed knowledge of IV vitamin as an effective anticancer treatment is finally coming to light with new research over the last decade. High dose IV vitamin C (ascorbate) 50-75 grams produces blood levels producing pro-oxidant effects acting in synergy with the oxidizing effects of Artemisinin, making both treatments more effective in killing cancer cells selectively without harming normal cells.(79) Since both high dose IV Vitamin C and Artemisinin are extremely safe, this highly effective synergy is considered the cornerstone of a successful anti-cancer protocol. This IV vitamin C bag may be followed by IV Alpha Lipoic Acid (300 mg IV) which shunts cancer cell metabolism towards aerobic respiration. The alpha lipoic acid heightens the Vitamin C effect as explained in my article on this topic. IV artesunate (avaliable as first line thereapy for severe malaria ) is commonly given IV just before the IV vitamin C. This augments the pro-oxidative effects.

Artemisinin-Curcumin Synergy

In a 2006 study using malaria infected cultured RBC;s, the combination of artemisinin with curcumin was found to synergize.(56) This combination showed greater malaria killing activity than the individual compounds. The molecular pathways were not elucidated. One might anticipate a synergistic effect for this combination in killing cancer cells. However, to my knowledge this has not yet been studied, and would be a good topic for NIH funding for future research.(56)

Artemisinin – Allicin (Garlic) Synergy

Synergistic Anticancer Effect Artesunate with Allicin OsteosarcomaAllicin,(diallyl thiosulfinate) the active ingredient in garlic, has known anti-cancer effects. Allicin induces caspase mediated apoptosis in lymphoma and other cancers. Dr Jiang (see Left Image) reported in 2013 the synergistic combination of Artesunate (artemisinin derivative) with allicin had a heightened anti-cancer effect on osteosarcoma cell lines in vitro and in vivo.(57) Left Image Fig 3B from Jiang showing synergistic effect of combining Artesunate (an Artemisin derivative) with Allicin. Bar Chart shows apoptosis levels after treating Osteosarcoma cells (in culture) with Artesunate (green arrow), Allicin (blue arrow) or combination of Artesunate and Allicin (Red Arrow). (57) Dr Jiang also reported additional mouse tumor xenograft studies were done, and these in-vivo studies also showed enhanced synergy for the combination of Allicin and Artesunate. (57)

Platelet Inhibition

Allicin,and thiosulfinates, are potent platelet-aggregation inhibitors which can aggravate bleeding, so caution is advised when used with other platelet inhibitors such as Feverfew, Aspirin, Vitamin E, Fish Oil or ibrutinib (Imbruvica – Bruton’s-Kinase Inhibitor).

Synergy Artemisinin with Resveratrol

Synergic effects of artemisinin and resveratrol in cancer cellsIn 2014, Drs Li and Yang reported a synergistic effect of the combination of Resveratrol with Artemisinin in Hepatoma (HepG2) and Cervical Cancer (HeLa) cell lines. The combination significantly increased apoptosis and necrosis of the two cancer cell lines. (58) Left Image Bar Chart from Li and Yang showing cancer cell death (apoptosis) after treatment with Artemisinin (green arrow), Resveratrol (blue arrow) and the Combination (red arrow) for two cancer cell lines (black and grey bars).(58)

Although Pterostilbene was not used in this study, the Pterostilbene is a derivative of Resveratrol, chemically similar with better bioavailability, and I would therefore expect Pterostilebene to demonstrate an even greater synergy with Artemisinin compared to Resveratrol. A 2005 study by Dr Tolomeo showed the 3-Hydroxy Pterostilbene to be 50-100 times stronger than Resveratrol in killing multi-drug resistance leukemia cells. However, the plain pterostilbene was the least toxic to normal hematopoetic cells. (59)

Synergy of Artemisinin with Butyrate (76, 122-128)

Synergistic Cytotoxicity Artemisinin Sodium Butyrate Human Cancer CellsDr Lai reports in 2005 that the cancer cell killing effect of Artemisinin is enhanced with the addition of butyrate, a short chain fatty acid.(76) Their study used a lymphoblastic leukemia cell line, treated with a combination of dihydroartimisin and butyrate.

Left Image Bar Chart courtesy of Dr Lai 2005, Cell Count after treatment with Dihydroartemisinin(Green Arrow), after Butyrate (blue Arrow), After Combination (Red Arrow)

In a 2007 report, Dr Pajak outlined the molecular basis of anti-cancer effects of butyrate. (123) Butyrate, a small four-carbon chain fatty acid, is a normal product of large bowel microbial fermentation of dietary fiber. Butyrate inhibits (HDAC) histone deacetylase activity, allowing DNA binding of several transcription factors which increases expression of proapoptotic genes, and results in amplification of apoptotic pathways (programmed cell su***de) in the cancer cell, while sparing normal cells.

In a 2013 report, Dr JK Fauser studied the anticancer effects of butyrate and coconut oil (lauric acid) on a colon cancer cell line. Dr Fauser reported butyrate induces apoptosis by:” inhibiting histone deacetylase activity, inducing cell cycle arrest, promoting differentiation, activating NF-κB, downregulating α 2 β 1 , modifying glucose availability, and inducing caspase activation in colon cancer cell.” (125)

Dr Choi reported in a 2006 study on the anti-cancer effects of butyrate on a leukemia cell line.(124) Dr Choi found that butyrate induced apoptosis of human leukemic cells by inhibition of telomerase activity. In addition, butyrate served as a (HDAC) histone deacetylase inhibitor, resulting in dose-dependent apoptosis associated with up-regulation in pro-apoptotic Bax expression, and down-regulation of anti-apoptotic Bcl-2 and Bcl-XL.(124)

In a 2006 report Dr Heider studied the effect of the HDAC, sodium butyrate, on three Mantle Cell Lymphoma types. Dr Heider reported butyrate induced potent programmed cell death (apoptosis) of all three Mantle Cell Lymphoma types in a dose-dependent manner. (136)

Buy Sodium Butyrate on Amazon. Link to a review. A probiotic named Clostridium butyricum is known to produce butyrate This is available from Japan in a product called “Miyarisan” available on Amazon. It is also contained in Advanced Orthomolecular Research AOR Probiotic 3.

Targeting (Progenitor) Cancer Stem Cells

Cytotoxic chemotherapy may be quite useful for controlling hematologic cancers such as lymphoma and leukemia. Although highly toxic, and frequently associated with adverse effects, these drugs may induce complete remission (CR), with disappearance of tumor masses and clearing of radionuclide activity on a follow up PET scans. In the more aggressive cell types, relapse with metastatic disease is inevitable. Relapse is thought caused by cancer stem cells (progenitor cells) which are dormant and not actively replicating. These cancer stem cells are insensitive (resistant) to cytotoxic chemotherapy which is not effective for non-replicating cells. (86-88) Are there natural non-toxic targeted therapies which target cancer stem cells?

Yes, and here they are a few of the many: Berberine, Resveratrol, Vitamin D3, Curcumin, Feverfew, and Sulforaphane. (89-90) These are natural substances that target cancer stem cells as discussed by Dr Yanyan Li in his 2011 article : which also includes soy isoflavone, epigallocatechin-3-gallate, lycopene, piperine, and vitamin D3. (134)

FeverFew – Targeting Cancer Stem Cells – Depleting Glutathione

The well known anti-migraine botanical , Feverfew (parthenolide) has been found to target the cancer stem cells.(74) The authors state:

“ Parthenolide preferentially targets AML progenitor and stem cell populations….The molecular mechanism of Parthenolide- with inhibition of nuclear factor κ B (NF-κB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of Parthenolide triggers Cancer Stem Cell-specific apoptosis and as such represents a potentially important new class of drugs for Cancer Stem Cell-targeted therapy.”(74)

Feverfew (Parthenolide) is a widely used botanical which exerts potent anti-cancer effects by blocking nuclear activation of Nuclear Factor Kappa Beta (NFKB), and depleting the cancer cell of glutathione, rendering it sensitive to ROS (reactive oxygen species) which triggers apoptotic pathways. (92-108) Parthenolide shares some similarities in chemical structure with Artemisinin. One might speculate that the two agents might work synergistically together with enhanced cancer cell killing effects, and this would be a good topic for NIH funding and future study. (92-108)

Sulforaphane – Targeting Cancer Stem Cells and Depleting Glutathione

The active ingredient in broccoli is sulforaphane, a widely used nutritional supplement with no adverse effects. Sulforaphane has been widely studied as an effective anti-cancer agent which targets cancer stem cells and depletes glutathione in the cancer cell, thus rending it more sensitive to oxidative damage.(109-115)

Dr Yanyan Li, et al reported in 2010 that sulforaphane eliminated breast cancer stem cells in vivo in a mouse xenograft model. Tumor bearing primary mice were treated with sulforaphane. The tumor cells from the primary mice were then re-implanted into secondary mice, showing no growth of tumor cells, indicating the cancer stem cells has been eradicated. (112) I was impressed by this. A 2012 study by Dr Rodova showed Sulforaphane is effective anti cancer treatment for pancreatic cancer stem cells via blockade of hedgehog signalling.(135)

Other Re-Purposed Drugs that may Work with Artemisisin:

Sulfasalazine_Ferroptosis_Cancer_Cell_CystineSulfasalazine (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 Chemotherapy – Rituximab

Rituximba Artesenuate synergy jeffrey dach mdLeft Image: Lymphoma Cell viability after (Black Arrow) Rituxumab , (Green Arrow) Artesenuate, (Red Arrow) combination of two. Synergy of Rituximab with Artesenuate from Sieber, Sebastian, et al. 2009 Combination Rituximab and Artesunate..

The anti-CD-20 monoclonal antibody, rituximab, has revolutionized the treatment of lymphoma, by targeting the CD20 protein on B cell lymphoma membranes, and increasing response and survival rates. Artemisinin has been given with rituximab with good synergism and increased anticancer activity. Dr Seiber says: “both agents act synergistically by activating at least partially converging signaling pathways.” 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 s***m counts.

Cannabinoid Extracts Have Anti Cancer Activity – See my previous article on the use of cannabis extracts in treatment of cancer. Cannabis extracts have a long history of beneficial use in chemotherapy patients for relief of nausea, and increase appetite effects. There is also a pain relief effect from cannabis extracts. Another unexpected benefit is the anti-cancer effects of cannabis are substantial, especially in Leukemia and Lymphoma cells which are specifically sensitive to cannabis extracts as they express increased CB1 and CB2 cannabinoid receptors. Numerous research studies show that Cannabinoid extracts and ligands induce apoptosis (programmed cell death) in cancer cells via ceramide accumulation. (30-38)

Is there synergism and augmentation of anti-cancer effects with cannabis extracts and artemisinin compounds ? Taken in together combination, would cannabis extracts increase the anti-cancer effect of artemisinin ? This would be a good topic for NIH funding of future research. My best guess is that future research studies will demonstrate this is indeed the case.

Medicinal Use of Cannabis Extracts have been approved in 23 states so far. If you reside in one of these states, then you may qualify as a medicinal cannabis patient and may legally obtain medicinal cannabis according to your specific state law. A reputable source for high quality medical grade cannabis oil is Mara Gordon of Aunt Zelda’s Dispensary in San Fransisco, California. (note: I have no financial relationship with Aunt Zeldas) . For more on information, see my book on Amazon: Cannabis Extracts in Medicine

Gleditsia sinensis – Korean thorn

This natural plant botanical has shown anticancer activity. Possible synergy with artemisinin might be explored. (60-61)

Ivermectin (62-68) (Stromectol for humans and Ivomec for Dogs)

heartgard_Dog_canine_ivermectinThe 2015 Nobel Prize in Medicine was awarded to William C. Campbell and Satoshi Ōmura for discovery of Ivermectin, the Wonder Drug From Japan, a well known anti-parasitic agent used to treat “billons” of pets and livestock around the world. (62-68)

Left image : Ivermectin (HeartGuard) for dogs. Image Courtesy of All Four Paws .

In humans, Ivermectin is well known as treatment for Lice (Pediculosis) and Scabies (Mites). Ivermectin also treats parasites such as Nematodes, Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis.

In 2010, Dr Sharmeen published his study. (62) He screened a long list of drugs looking for cytotoxicity to leukemia cells, and discovered ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines, while sparing normal cells. He then studied three mouse models of leukemia showing that tumor growth was delayed “at drug concentrations that appear pharmacologically achievable“(62)

Dr Sharmeen reported ivermectin blocks the glutamate-gated chloride channels, increases intracellular chloride ion concentrations and cell size of leukemia cells. This causes plasma membrane hyperpolarization. Ivermectin also increased (ROS) reactive oxygen species in cancer cells functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with conventional chemotherapy agents, ARA-C (cytarabine) and Adriamycin (anthracycline drug also known as Daunorubicin) to increase ROS, reactive oxygen species production. (62)

Ivermectin Cancer Cell Death MechanismAbove image: mechanism of Ivermectin induced caner cell death from Fig 7 Model of P2X4/P2X7/Pannexin-1-induced cancer cell death. Draganov 2015

Dr Dobrin Draganov reported in 2015 that Ivermectin “kills mouse and human triple-negative breast cancer (TNBC) cells through augmented P2X7-dependent purinergic signaling associated with caspase-1 and caspase-3 activation.” …”also involved is the recruitment and activation of T cells, macrophages and dendritic cells, a form of immunomodulation and cancer immunotherapy.”

In 2014, Dr Alice Melotti reported that Ivermectin inhibits the WNT‐TCF pathway in cancer cells. further elucidating the molecular mechanism of cancer cell death.(130) In a colon cancer cell model, Dr Melotti found Ivermectin effective at micromolar concentrations against both tumor bulk as well as cancer stem cells. The authors suggested ivermectin,” might be useful as a routine prophylactic agent, for instance, against colon cancer in familial polyposis, or to prevent nascent cancer in the general aging population.” (130) I was astonished by this statement.

Ivermectin Effective Against Ovarian Cancer Cell Line

In 2009, Dr Hashimoto showed Ivermectin Effective against ovarian cancer cell lines. (152) “Ivermectin inactivates the kinase PAK1 and blocks the PAK1-
dependent growth of human ovarian cancer and NF2 tumor cell lines” 152.

Targeting WNT Eliminates Cancer Stem Cells

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.

Artemisinin Synergy with Alpha Lipoic Acid ?

Alpha lipoic acid (ALA) and artemisinin infusions are commonly given together as part of a comprehensive cancer treatment. Alpha Lipoic acid may work in synergy with the artemisinin, causing oxidative damage to mitochondria and inducing mitochondrial apoptoosis in the cancer cell.

Artemisinin Targets Cancer Stem cells

Two studies suggest artemisinin compounds down regulate the WNT pathway and targets cancer stem cells in the lung tumor and brain glioma cell models .(154-155) In a colorectal cancer cell study, Artemisinin was found to strongly inhibit the WNT/Beta Catenin pathway, suggesting utility as a stem cell agent. (157) Indeed, in 2016, Dr Amit Subedi and Dr Nishi reported “High-throughput screening identifies artesunate as selective inhibitor of cancer stemness: Involvement of mitochondrial metabolism.” (163)

Artemisinin Downregulates Nuclear Factor-Kappa Beta and Inflammatory Cytokines- PI3 kinase/Akt signal pathway

A number of studies show striking downregulation and inhibition of the major inflammatory transcriptor, NF Kappa Beta and downstream signalling pathway such as c-Myc and Cyclin D1. There was striking synergy between lenalidamide and artemisinin when used together(158-160)(170-171)

Dr Xu showed artesunate inhibits TNF-α-induced production of proinflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes.” (158) A number of PI3K inhibitors anti-cancer drugs in development such as buparlisib and Idelalisib target this same PI3 kinase/Akt signal pathway inhibited nicely by artesunate. (161)

In an endometrial cancer model, Dr Tran revealed the exact mechanism of NF-kB inhibition.(171) The p65 and p50 are subunits of the NF-kB protein residing in the cytosol. Artemisinin prevents p65 and p50 nuclear translocation by interacting with IκB-α, the NF-κB inhibitor, leading to a loss of CDK4 gene expression.(171)

Artesunate Striking Inhibition of WNT Pathway in SKM Cells

Below Image is Fig 5. from Xu (162). LSCM was used to detect E-cadherin and β-catenin subcellular localization. Cells were fixed after different concentration of ART treatment for 48h, and stained with A. E-cadherin and B. β-catenin. Pictures were taken by LSCM (scale bar = 35µM). a-d represents different concentrations of Artesunate (a=0µg/mL, b=12.5µg/mL, c=25µg/mL, d=50µg/mL). Blue Arrow indicates Nuclear location of E-cadherin (left panel) and β-catenin (right panel). Red arrows indicates membrane locations for both.

Artesunate Induces SKM Apoptosis ß-catenin



In 2015 Dr Na Xu studied the effect of Artesunate on SKM-1 cells in vitro, a model for Myelodysplastic Syndrome.(162) Dr Na Xu found “ART treatment inhibited Wnt/β-catenin downstream expression of targets such as c-myc and cyclinD1.” When SKM-1 cells were treated with Artesunate, both β-catenin and E-cadherin translocated from the nucleus to the membrane, thereby forming the β-catenin/E-cadherin complex and strengthening cell-cell adhesion.(see above image )(162)

Similar translocation of Beta-Catenin from cell nucleus to outer membrane was seen in a colo-rectal cancer model reported by Dr. Lin-Na Li in her 2007 study,”Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/β‐catenin pathway.” (157)

Inflammatory Signals From Micro-Environment in Mantle Cell Lymphoma

In Blood 2012, Dr Liang Zhang studied the role of the microenvironment in mantle cell lymphoma. Dr Zhang found that the inflammatory cytokine IL-6 activated the Jak2/STAT3 and PI3K/Akt pathways in MCL, mantle cell lymphoma. IL-6 is a key cytokine for MCL growth and survival. (176) Dr Lai reports in 2003 J Pathology that STAT3 (signal transducer and activator of transcription 3) is the signal transducer of IL-10 another cytokine which is upregulated in the tumor micro-environment, and this induces proliferation in Mantle cell Lymphoma.(177)

Artesunate down-regulated the expression of STAT3 in leukemia

Dr Mei Tan in 2017 Leukemia Research wrote: “Artesunate induces apoptosis via inhibition of STAT3 in THP-1 (leukemia) cells.” (179) Dr Tan found that 30 leukemia patients had significantly increased STAT3 protein levels compared to controls. In addition, Artesunate significantly inhibited the proliferation of leukemia cells, and increases apoptosis, by down-regulating STAT3.(179) Similarly in a hepatocellular cancer mouse model, Artesunate obliterated the cancer by suppressing IL-6-JAK-STAT signalling (180) In 2007, Dr Xu reported that artesunate inhibits TNF-α-induced production of pro-inflammatory cytokines via inhibition of NF-κB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes.” (181)

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. Another useful effect of Artesunate is down-regulation inflammatory pathways needed for cancer cell proliferation.

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.

Update Sept 2017: Synergy of ALA (Aminolevulinic Acid) with Artemsinin, which increases activity ten times. See : Wang, Jigang, et al. “Mechanistic investigation of the specific anticancer property of artemisinin and its combination with aminolevulinic acid for enhanced anticolorectal cancer activity.” ACS central science 3.7 (2017): 743-750.(172) ALA is precursor molecule for heme synthesis, allowing the cancer cells to make more heme which is then reactive with the Artesunate/Artemisinin. Note: ALA was FDA approved June 2017 as a photo-imaging tool during neurosurgery for malignant glioma. The patient takes an oral dose of Gleolan 3 hours before surgery, allowing fluorescent visualization of tumor at surgery.(172-175)

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. For part three click here.

Financial Disclosure: I have none. I receive no monetary inducements from, nor have any financial interests in any manufacturer of artemisinin products. I do however receive stipends from Amazon for links to products on this page.

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