Antimalarial Artesunate’s potential against cancer
Artemisinin or Qinghaosu (青蒿素), derived from the leafy portions of the sweet wormwood plant Artemisia annua L. or qinghao (青蒿), and isolated in 1972 by Chinese chemists, is a potent anti-malarial that has revolutionized modern malaria treatment. What makes this and related bioactive derivatives super interesting is that they exhibit potent anticancer effects in a variety of human cancers (Expert Rev Mol Med. 2009 Oct 30;11:e32), a fact which has been known for almost three decades but relatively unexplored.
In Vitro and in Vivo Research
One of the most notable semi-synthetic derivative drug from artemisin is artesunate (ART), which was developed for malaria in the 1980’s was noted to have anti-cancer activity along with other artemisinins by the early 1990’s (J Nat Prod. 1993 Jun;56(6):849-56), with Lai and Singh reporting that artemisinin selectively killed MOLT-4 lymphoblastoid leukemia cells in 1995 (Cancer Lett 1995; 91:41-46). Subsequent research by Thomas Efferth’s team in Germany demonstrated artesunate’s in vitro efficacy against multiple tumor lines (Int J Oncol. 2001, 1:767-773) and was most active in vitro against leukemia and colon cancer while modestly effective against melanomas, breast cancer, ovarian cancer, prostate cancer, glioma, and renal cancer. The same research team was also responsible for elucidating much of the molecular mechanisms of efficacy of ART against cancer, which included direct cytotoxicity, anti-angiogenesis as well as induction of apoptosis (See Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97).
Beyond the test-tube, it has been found that ART (as well as artemisinin and other artemisinin derivatives) can successfully treat grafted human tumors in laboratory animals (Biochem Pharmacol 2004 Dec 15;68(12):2359-66), and this lead to Efferth’s group to attempt to treat two uveal melanoma patients after chemotherapy has failed. Generally, such cases have a median survival of 2-5 months, but with ART treatment, one patient went on to live 24 months and the other patient is alive at 47 months (as of 2007) after initial diagnosis of stage IV melanoma. Other clinical reports include the successful use of artemether, a related compound, in the treatment of a pituitary macroadenoma (Integr Cancer Ther. 2006 Dec;5(4):391-4) and a report of a 72 year old gentleman in India with laryngeal squamous cell cancer, which responded nicely to ART alone with a 70% shrinkage over 2 months (Arch Oncol 2002; 10(4):279-80). In China, a clinical trial comparing ART + chemo vs. chemo alone against non-small cell lung cancer found a modest improvement of the time to progression in ART treated patients (Zhong Xi Yi Jie He Xue Bao. 2008 Feb;6(2):134-8) despite the fact that lung cancer is one of the least sensitive cell lines to ART when tested in vitro. Anecdotally, dogs with bone cancer and lymphosarcoma have been reported to rapidly respond to artemisinin, and patients with prostate cancer, brain tumors, pancreas cancer, breast cancer were also anecdotally reported to have been helped by artemisin derivatives. Reportedly, Dr. N. Singh from the U. of Washington mentioned the case of a man with brain cancer who has been in coma for 5 months who came out of the coma after 21 days injections of artemether, a related compound. (See newsletter article by Christina White, “Cancer Smart Bomb, Part I & II: An Idea from Ancient Chinese Medicine”, New Horizons, Summer & Fall 2002 issues published by the Brewer Science Library -> an online excerpt is available).
In Germany, a trial of ART against breast cancer is currently recruiting at the University of Heidelberg and there was also a phase I trial in the U.K. against colon cancer that was completed but unpublished.
ART is largely non-toxic, with related compounds having been administered to over 2 million patients, children and adult, world-wide without significant concern for serious adverse effects reported (Trans R Soc Trop Med Hyg. 1994: 88 (Suppl 1):S3-4.) and ART is cheap compared to conventional cancer drugs, but then why aren’t there more trials or more wide-spread use of ART as an off-label cancer treatment? The usual combination of ignorance (most conventional oncologists I have spoken with not even unaware of artemisia or artemisinin or ART’s potential against cancer, and some have never heard of a drug called artesunate) and commercial interests (or lack of interest rather) are the culprits here hampering an advance. Furthermore, in the specific case of ART, its highly restricted availability is also contributory (believe it or not, in the USA, it was only in 2007 that the FDA approved investigational new drug (IND) protocol # 76,725 for the use of artesunate in treating “severe malaria”, making it the first time that any of the artemisinins are legally available as a drug in the US. Currently, the US army (Walter Reed Army Institute of Research) supplies ART to the Center of Disease Control (CDC) which is in turn the only legitimate source of the drug in the US, and even then, it is only available to hospitals, upon request and on an emergency basis, by the CDC ! (See CDC website for ART availability details). Worldwide, genuine oral ART is also difficult to obtain due to WHO concerns and constraints secondary to surging malaria resistance to one of the last remaining effective anti-malarials, compounded by a problem of rampant distribution of fake ART in third world countries.
Despite some concern for neurotoxicity based on animal studies, ART and related compounds are some of the least toxic medications on the market for any condition, without clinically relevant toxicity after extensive oral and parenteral use in various populations for the past two decades, except for sporadic and transient cardiac dysrhythmias. These compounds are also relatively inexpensive, being dispensed mainly in the third world in poor populations where malaria is endemic. With the demonstrated bioactivity in the laboratory and the promising anecdotal cases, these seem to be perfect compounds to try against cancers , either in combination or when other treatments fail. It is hoped that regulatory authorities could loosen the grip on dispensing of ART and related medicines, especially where malaria or malaria resistance is not a concern in the territory (e.g. in the US or Western Europe, Japan) to allow cancer patients a compassionate avenue to the treatment especially when other treatments have failed.
My research group at the Institute of East West Medicine here in New York have noticed the potential of anti-malarials against cancer in general and we are currently exploring other naturally derived anti-malarials as possible anti-cancer agents with generous support from the Gray Charitable Trust and other private supporters. Funding permitting, semi-synthetic and synthetic derivatives of artemisinins could also be systematically explored and developed with a use against cancer in mind, and combinations of ART with other anti-cancer agents to achieve synergies should also be urgently investigated.