[The Sino Med Research Institute does not advocate the use of artemisinin and its derivatives to treat disease. Although it is recommended by the World Health Organization as a treatment for malaria, the U.S. Food and Drug Administration (FDA) does not currently approve the use of artemisinin and its derivatives for the treatment of any disease. Research on artemisinin and its derivatives and cancer is still in the very early stage. Human use of them should be considered experimental and taking artemisinin or its derivatives and any supplements should be approached with caution. If you are seeking treatment for any medical disease, please consult a qualified health care professional.]
Artemisinin, Its Derivatives and Cancer
Qingcai Zhang
Sino-Med Research Institute
New York
1. From Malaria to Babesia to Cancer
Artemisinin is an active ingredient extracted from the traditional Chinese medicinal herb Qing Hao (Herba Artemisiae annuae), a sweet wormwood plant. In more than three decades, Artemisinin and its molecule-modified derivatives, such as artesunate, have undergone extensive basic and clinical studies for its anti-malaria effects. As a result, the World Health Organization has stated artesunate as the first line treatment for malaria. Since then, millions of malaria patients have been successfully treated with artesunate and it was also shown to be effective in cases of drug-resistant malaria. Articles are available documenting the extensive pre-clinical and clinical studies that have been done. (Bharel S, et al., 1996, Gulati A et al., 1996) Babesia is a malaria-like protozoa infection of the red blood cells and a common co-infection of Lyme disease. In Zhang Clinic, we have found artesunate to be an effective treatment for Babesiosis as well. Current research on artesunate is starting to reveal its potentials in cancer treatment. (Efferth T, et al., 2001) Currently, Zhang Clinic is using artesunate as a non-toxic adjunctive treatment for supporting the health of cancer patients.
2. Pre-Clinical Studies— Anti-Malaria, -Babesia, and -Cancer Mechanisms
The mechanism of anti-malaria and babesia protozoa action of artemisinin and its derivatives is speculated to be related to the iron metabolism of protozoa. Its molecular peroxide group produces reactive oxygen atoms, which can interfere with the iron metabolism of protozoa. Iron is required for cell division as cancer cells can aggressively accumulate iron for their rapid cell reproduction. Artemisinin and its derivatives can interfere with this type of abnormal cell reproduction and promote the cell to enter apoptosis (Schaller J, 2006). Artemisinin and its derivatives have been shown to affect oxygen and carbon based free radical mechanisms. Its structure includes an endoperoxide bridge. Peroxides generate free radicals in a Fenton type reaction when exposed to unbound ferrous iron. Malaria and babesia invade and grow in erythrocytes (red blood cells), have the opportunity to accumulate excess iron, which can spill into the unbound form. Electron microscopy has confirmed the destruction of plasmodium membranes with morphology typical of free radical mechanisms. Knowing that there is a high accumulation of iron in cancer cells, researchers Henry Lai and Narenda Singh of the University of Washington became interested in the possible positive effects artemisinin may have against malignant cells. In 1995, they published a paper in Cancer Letters regarding the use of artemisinin against numerous cancer cell lines in vitro. This article has mobilized interest in artemisinin as an addition to cancer treatment. (Lai H et al., 1995). They further confirmed this theory and reported that artemisinin-tagged holotransferrin can enhance the selective cancer cell killing effects of artemisinin and were not toxic to normal cells. Lai and Singh found that after tagging artemisinin to transferrin, both iron and artemisinin would be transported into cancer cells in one package. Once inside the cell, iron is released and can readily react with the artemisinin tagged to the transferrin. This in turn, enhanced the selectivity of artemisinin’s effects on cancer cells. This was then tested on a human leukemia cell line (Molt-4) and normal human lymphocytes. It was found that the holotransferrin-tagged artemisinin was both potent and selective in killing cancer cells, and did not cause harm to normal cells. Thus, it was concluded that the 'tagged-compound' could potentially be developed into an effective chemotherapeutic agent for cancer treatment (Lai H et al., 2005).
Another anti-cancer effect of artemisinin and its derivatives is the ability to promote cancer cells to enter apoptosis (programmed cell-death). Increasing the amount of iron in cancer cells could enhance this effect. Singh NP et al. reported that cancer cell lined Molt-4 cells were first incubated with 12 microM of human holotransferrin to enhance the iron supply to the cells. The cells were then pelleted and transferred to a culture media containing 200 microM of a derivative of artemisinnin, dihydroartemisinin (DHA) and then incubated. It was found that DHA treatment significantly decreased cell counts and increased the proportion of apoptosis in cancer cells compared to the controls (chi2=4.5, df=l, p<0.035). The addition of holotransferrin further decreased cell counts significantly (chi2=4.5, df=l, p<0.035) and increased apoptosis (chi2=4.5, df=1, p<0.035). No necrotic cells were observed. It was concluded that the rapid induction of apoptosis in cancer cells after treatment with DHA indicates that artemisinin and its derivatives may be effective anti-cancer agents (Singh Np et al., 2004).
One of the derivatives of artemisinin, deoxyartemisitene, has been tested to have the effects to suppress 14 different types of human cancer cell lines. (Galal AM, et al., 2002) The following cancers were shown to have the highest sensitivity to these substances: leukemia, colon cancer, and melanoma. (Berger TG et al., 2005, Efferth T, et al., 2002) It has also shown suppressive effects on following cancers: breast cancer, ovarian cancer, prostate cancer, brain cancer, kidney cancer and others. (Efferth T, et al., 2006, Anfosso L, et al., 2006, Paik IH, et al., 2006, Galal AM, et al., 2002, Lee CH, et al., 2000, Singh NP, et al., 2001) Similar anti-cancer activities have also been found in other derivatives of artemisinin, such as arteether, artemether and dehydroartemisinin (Singh NP, et al., 2001).
Cell cultures of drug-resistant breast cancer were found to have a high propensity of iron accumulation. When these iron-loaded cells were treated with artemisinin, 75% died within eight hours and nearly 100% died within 24 hours. In the control, normal cell cultures without heavy iron loads were not affected. (Singh NP, et al., 2001, Lai H, et al., 1995) Thus, the existence of heavy iron load seems to be a condition required for artemisinin and its derivatives to suppress cancer cells. This has been confirmed in animal studies. (Moore JC, et al., 1995) and it is believed that the main cancer suppressing mechanism of artemisinin and its derivatives is in the peroxide-oxygen spark that occurs inside the cancer cell. (Schaller J, 2006, Efferth T. et al., 2006) The current theory is that if we can increase cellular iron load by using a method such as holotransferrin then the efficacy of cancer treatment by these derivatives, especially dihydroartemisinin, can be enhanced. (Singh NP, et al., 2001) Another possible mechanism is that these substances can combine with and alter the functions of certain proteins unique to cancer cells. (Lee CH, et al., 2000) These effects work together to promote cancers cell entering apoptosis. (Singh NP, et al., 2004).
Artesunate is a semi-synthetic derivative of artemisinin, and has been analyzed for its anti-cancer abilities against 55 types of cancer cell lines by the Developmental Therapeutics Program of the National Cancer Institute, USA. (Efferth et al., 2001) Artesunate demonstrated dramatic cytotoxic activities against a wide variety of cancers including drug resistant cell lines. Artesunate was shown to be most active against leukemia and colon cancer cell lines. The mean 50% growth inhibition (GI50) concentrations for them were 1.11microM and 2.13 microM respectively. Non-small cell lung cancer cell lines showed the highest mean (GI50 26.62 microM) indicating the lowest sensitivity towards artesunate. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Most importantly, a comparison of artesunate’s cytotoxicity with currently used cytostatic drugs showed that artesunate was active in micro molar ranges comparable to those of established anti-tumor drugs. Leukemia lines resistant to doxorubicin, vincristine, methotrexate, or hydroxyurea were tested. Remarkably, none of these drug resistant lines showed resistance to artesunate. The theorized reason for this is the absence of a tertiary amine in artesunate (required for cellular transport systems to usher the drug outside the cell), which is present in virtually all currently used chemotherapy drug agents. (Rowen R, 2002).
Cancer cells are deficient in antioxidant enzyme superoxide dismutase. The manganese in mitochondria and copper zinc in cell cytoplasm are generally lower in cancer cells. Cancer cells are also grossly deficient in catalase and glutathione peroxidase, both of which degrade hydrogen peroxide. It is the deficiencies in antioxidant enzymes lead to the use of many types of common chemotherapeutics that are superoxide generators. The higher iron fluxes, especially associated with the mitosis phase of cancer cells, should render these cells more susceptible to oxidative damage via hydrogen peroxide and superoxides. Normally, the profound catalase deficiency in cancer cells is credited with creating vulnerability to oxidants. However, since all of these protective antioxidant enzymes are often deficient in transformed cancer cells, the oxidant vulnerability is dramatically enhanced due to unbound iron during cell division. This is one of the anti-cancer mechanisms of artemisinin and its derivatives (Levine SA, et al.,1985).
3. Clinical Observations
Clinically, Dr. NP Singh has been following a series of cancer patients with nearly universal improvement while being treated by artemisinin or its derivatives. He believes that artemisinin will prove to be one of the most powerful therapeutic agents in cancer treatment. He emphasizes that it should be used in a professional medical settings together with complementary strategies employing detoxification, diet, immune support, and spiritual work. The Dr. Hoang has observed a 50-60% long-term remission in over 400 cancer patients utilizing artemisinin together with a comprehensive cancer strategy, and with no observed toxicity (Rowen R, 2002).
In Zhang Clinic, we have been using artesunate for treating pre-cancerous conditions. Three cases of biopsy-confirmed stomach intestinal epithelium metaplasia, which is a pre-cancerous condition of stomach cancer, treated with Artemisia Capsule (contains artesunate 33.3 mg per capsule) three times a day for two months. Subsequent GI biopsies found that the metaplasia was no longer there. In several patients diagnosed with cervical dysplasia by PAP smear, Allicin Capsule and Artemesia Capsule (both used as vaginal suppository) was used for several weeks. In every case, follow-up PAP smear checks for dysplasia turned to negative.
In patients with cancer diagnoses or those already finished with conventional oncology treatments, Artemisia Capsule was used as adjunctive supporting treatment. We have seen promising results in treating hepatocellular carcinoma (HCC), breast cancer, lymphoma, multimylenoma, urine bladder cancer, and oral cancers. In those patients whose major cancer lesions were treated by oncologic therapies but still had untreated lesions, the artesunate treatment was able to stabilize and shrink the smaller lesions. For those patients who had main cancer lesions removed by surgery, chemotherapy, or radiotherapy, artesunate treatment was used as a preventive measure for possible relapse and metastasis. Combining with other traditional Chinese medicine (TCM) herbal formulas were used as supportive agents to improve the patient’s survival and life quality.
Since artemisinin and its derivatives, such as artesunate, have a wide anti-cancer spectrum, they have been clinically tested for treating following various common cancers.
Hepatocellular Carcinoma (Liver Cancer):
Our clinic has been treating many patients with viral hepatitis B and C. Patients in the advanced stages are at risk for developing HCC. We use artesunate (active ingredient of Artemisia Capsule) as the main treatment agent. In some of these patients, lesions have been treated by surgery or trans arterial chemo-embolism (TACE) and alcohol or radiofrequency ablation. When they initially came for treatment, every patient had untreated HCC lesions in their liver. After artesunate treatment, most of these lesions became stabilized and some scattered smaller lesions disappeared. In addition, we also focus treatment on restoring liver function and controlling liver inflammation. From our clinic experience, every HCC patients showed longer than expected survival time while overall life quality was improved.
The following are two patient case studies:
Case 1
Fran was 73 when she first visited Zhang Clinic on Dec. 14, 2000. She had been diagnosed with hepatocellular carcinoma (HCC) and hepatitis C in the de-compensated cirrhosis stage. Symptoms included light jaundice, gallstones, elevated ammonia (69.8), leukopenia (WBC 2.3), anemia, low platelets (60), mild ascites and edema, liver inflammation, and bile retention. She had severe fatigue and insomnia. A physical check also showed an enlarged spleen consistent with portal vein hypertension. In addition to the liver conditions, Fran also had type II diabetes. Following an MRI performed on Nov. 8, 2000, two lesions were found on her liver: one high in segment 8 measuring 2.9 x 3.0 cm; the other in segment 6, which was slightly exophytic, and measured 3.7 x 3.4 cm.
Fran was treated at the Sloan - Kettering Institute. The treatments consisted of embolism on both lesions and alcohol ablation on the lower lesion. The higher lesion was not treated with ablation due to its location being too close to the lung. She was also physically too weak at that time to tolerate ablation treatment for both lesions. As her treatment options were limited, she came to Zhang Clinic seeking alternative methods. Our treatment goals focused on restoring her liver functions and controlling the cancer. The R-6532 Capsule, a modified version of TCM formula Kang Ai Bao (Wang HZ et al. 1997) was used along with a liver supportive protocol. After 3 months on treatment, Fran’s liver functions had improved, jaundice cleared, ascites and edema eliminated, and the ammonia levels normalized. A CAT scan performed on July 19, 2001 revealed that the size of the higher lesion had decreased to 1.1 x 1.1 cm (from 2.9 x 3.0 cm) and the lower lesion had decreased in size to 2.7 x 2.3 cm. (from 3.7 x 3.4 cm). No new lesions were detected. Thereafter, a CAT scan was done every 6 months. On Dec. 18, 2003, new lesions were discovered in segment 7 and 6. At this time, Fran’s general health and liver functions were strong enough to tolerate embolism and alcohol ablation treatments and were successfully completed. Since then, we have added artesunate (Artemisia Capsule) in her protocol to treat residual cancer cells and help prevent possible relapse. Fran is now 81 and enjoys a good life quality despite her compromised liver functions 8 years after the HCC diagnosis. Her lesions are checked every 6 months and have been stable.