Artemisinin is the first line drug used for the treatment of uncomplicated Plasmodium falciparum malaria worldwide. It was first isolated from the plant, Artemisia annua which had been a historic herb in China over 2000 years.
Artemisinin has a peroxide bridge which gives it the ability to form free radicals after reacting with iron. These free radicals are toxic to cells. Cancer cells are highly dependent on iron for the replication of DNA during cell division. Therefore these cells contain a high concentration of intracellular iron than do normal cells to supply their demand of out of control cell proliferation. Thus, artemisinin has selective toxicity to cancer cells.
The discovery of this function of artemisinin broadened the scoop of research towards anti-cancer therapy. However, simple artemisinin is less potent than common anti-cancer drugs and it would require a high dosage to reach the desired therapeutic effect. Using a high concentration of the drug can induce the dose-related side effects. Therefore, more effective artemisinin derivatives are being designed and used for clinical trials and research. They have given promising results as more potent drugs with a less side effect profile in comparison to the traditional anti-cancer agents.
Many derivatives of artemisinin; both simple and complex have already been tested for the treatment of several common cancers affecting humans. Hepatocellular cancer is one of them.
Hepatocellular cancer has a long latency period with no presenting symptoms or complications. Therefore most patients have advanced disease with high grade tumors and local and distant spread at the time of the diagnosis. This results in a very low 5 year survival rate in most instances.
Treatment options for hepatocellular cancer include surgical resections and chemotherapy. However surgical interventions may not be possible with advanced tumors. Therefore pharmacological therapy is of paramount important in the management of hepatic cancer. Traditional chemotherapeutic drugs are not much effective for advanced cancer even when used in combination. This gives rise to the pressing need of identifying alternative treatment options.
Gemcitabine is a newly identified broad spectrum anti-cancer drug that has been evaluated in clinical trials for the treatment of hepatic cancer. These studies have given positive results so far. Further research studies are conducted with this drug in combination with artemisinin and its derivatives.
Anti-cancer action of artemisinin is thought to be mainly due to induction of apoptosis (cell death). However, detailed mechanisms are yet to be defined.
One research was carried out in China where hepatocellular carcinoma burden is high by Dr. Junmei Hou and others. In this study, artemisinin (ART) and its derivatives dihydroartemisinin (DHA), artemether (ARM) and artesunate (ARS) were tested in vitro against hepatoma cells HepG2 (p53 wild type), Huh-7 (p53 mutant), BEL-7404 (p53 mutant), Hep3B (p53 null) and 7702 (normal human liver cells). The effect on cell viability exerted by each artemisinin derivative on these different cell types were compared. In addition to this, the effect of ART and DHA alone and in combination with gemcitabine on HepG2 and Hep3B were further evaluated in vitro and in vivo. Among the four artemisinins, ART and DHA had the greatest cytotoxic effect on hepatoma cells while having significantly lower cytotoxicity on normal liver cells. The basic mechanisms involved in this processes were inhibition of cell proliferation, G1 phase arrest and modulation of other molecules of the cell cycle. They also act by inducing apoptosis, inhibiting tumor growth and modulating tumor gene expression both in vitro and in vivo. In addition to these effects, DHA also increases the anti-cancer efficacy of gemcitabine. The investigators of this extensive research concludes that “ART and DHA have significant anticancer effects against human hepatoma cells, regardless of p53 status, with minimal effects on normal cells, indicating that they are promising therapeutics for human hepatoma used alone or in combination with other therapies”.
Another research was conducted by Dr. Y.P Vandewynckel and others in 2014 to find the therapeutic effect of artesunate in hepatocellular cancer. The main objectives of this research were evaluation of the effect on tumor growth, angiogenesis (new blood vessel formation), unfolded protein response and chemo resistance of hepatocellular cancer. Several hepatoma cell lines were tested under normoxic and hypoxic conditions both in vitro and in vivo. Histological studies, enzyme assays and advanced imaging modalities were used in this study. The results indicated that artesunate has dose dependent action on reducing cancer cell viability. Hypoxic conditions enhanced these effects. Artesunate also down regulated the vascular endothelial growth factor (which is important for angiogenesis) and reduced the tumor bulk. The in vivo effects were enhanced by the combination of sorafenib. No apparent hepatotoxicity was evident during these reactions. And artesunate did not induce chemo resistance with doxorubicin. This research also concludes that artesunate is a potential treatment option for hepatocellular cancer.
Another interesting study done by Dr. Henry Lai and others made use of the fact that cancer cells express a large number of transferrin receptors on their surface. Transferrin is the iron transporter in blood. Transferrin, once bound to its receptor is taken into the cell by the process called endocytosis. Therefore, if artemisinin is tagged to transferrin, this complex would be selectively taken up by cancer cells leading to a high concentration of artemisinin tagged transferrin. Inside the cell, iron will then be released from transferrin and the reaction between iron and artemisinin produces free radicals which kill the same cancer cell. The researchers emphasizes the high selectivity and potency of artemisinin tagged transferrin in killing cancer cells.
More facts are found in an article titled “Chinese Herb Cures Cancer” by Dr. Robert Jay R Rowen published in 2002. According to this article, a doctor from Vietnam has achieved 50 to 60 percent long term remission rates (out of 400 cancer patients) when artemisinin was used in combination with standard cancer therapies. Among these patients, a 47 year old woman, who had terminal liver cancer complicated with ascites had the life expectancy of days to a few weeks. She was treated with artemisinin combination treatment and was alive two and half years later with no signs of the disease. This incidence gives strong evidence that artemisinin treatment can stabilize cancer growth effectively.
A recent study was done in 2013 with a novel artemisinin derivative named AD1-AD8 on in vitro hepatic cancer models. It also concludes that this compound is potential useful as an anti –cancer agent and the necessity of further animal studies.
All above studies are indicative of artemisinin’s ability to reduce the main cancer focus of hepatocellular cancer. A different study evaluated the effect of the drug on invasion and spread in hepatoma cancer cells. Several cancer cell lines were treated with different concentrations of artemisinin. Results of this study indicated a concentration dependent inhibitory effect on tumor metastasis both in vitro and in vivo. Several biochemical mechanisms which include MMP2 metalloproteinase, TIMP2 protein (metallopeptidase inhibitor) and Cdc42 cell division control protein bring about these effects.
Thus, many research studies give a strong recommendation for the use of artimisinin and its derivatives as anticancer agents in hepatoma as it is effective for tumor cell apoptosis, tumor bulk reduction and tumor spread inhibition. It is further recommended that combination therapy is better than mono-therapy. However, further human studies are required to evaluate the efficacy of the drug and to identify the side effects in the long run before it is commercially manufactured.
Written by Dr. Minirisi Gunathilaka