Anticancer activity of Artemisinin

by Artemisinin H. Sweat Wormowd, artemisinin research

Cancer remains as a life-threatening disease and a leading cause of death as its control has been difficult. Although, a range of conventional therapies based on chemotherapy, surgery, and radiotherapy are available, these approaches are in many cases of limited efficacy. The main issue lies in formulating therapy with high specificity to cancer cells with little or no side effects on normal human cells. Many research projects have been focused on developing new anticancer agents either by exploring the anticancer ability of novel compounds or by assessing drugs conventionally used in other clinical diseases. One the promising compounds is artemisinin and its derivatives

Artemisia or sweet wormwood originates from Asia and has been used in China to treat fevers for more than 2000 years. It is a naturally occurring antimalarial which have shown potent anticancer activity. It is an endoperoxide compound extracted from this Chinese Herb qinghaosu. It has long been used as antimalarials with no significant side effects.

The wormwood extract was used centuries ago in China, but the remedy was misplaced over time. In the 1970s, it was rediscovered as part of an ancient manuscript containing medical remedies, together with a recipe that used a wormwood extract. Artemisinin combats malaria because the malaria parasite collects excessive iron concentrations as it metabolizes hemoglobin within the blood. Since some cancer cells, particularly leukemia cells, also have high iron concentrations, they may also be killed by artemisinin, as has been demonstrated in some initial studies with cancer cells in tissue culture. The compound is so selective for cancer cells partly due to a result of their rapid multiplication, which requires high quantities of iron, and partly because cancer cells are not as good as healthy cells at cleaning up free-floating iron.

Artemisinin is also a robust apoptogen and can potentially trigger targeted programmed cell death to cancer cells. Cancer cells require iron to replicate their cellular structures when dividing. The iron will get in by way of a protein channel known as transferring. In general, all cancer cells have higher nutritional demand including iron to sustain all the dividing they do. Sweet wormwood contains endoperoxide known as artemisinin which interacts with intracellular iron turning the iron into a potent free radical, which reacts with components of the cancer cell to tirgger devastating damage which eventually activates programmed cell death or apoptosis. It has been hypothesized that iron-activated artemisinin induces damage by release of highly alkylating carbon-centered radicals and radical oxygen species. Radicals may play a role in the cell alterations reported in artemisinin-treated cancer cells such as enhanced apoptosis, arrest of growth, inhibition of angiogenesis, and DNA damage. Tumor cells have enhanced vulnerability to ROS damage as they exhibit lower expression of antioxidant enzymes such as superoxide dismutase, catalase, and gluthatione peroxidase compared to that of normal cells. Hence, increasing oxidative stress is one of the anticancer mechanism of antitumor agents

Cancer cells exhibit an increase in transferrin receptors (TfR) which are responsible for the iron uptake and regulation of intracellular concentrations. Levels of expression of TfR in cancer cells may vary depending on the cell line. However, they differ substantially from normal cells leading to a high selectivity index of artemisinin and its derivatives. For example, Efferth et al. reported that leukemia and astrocytoma cells express TfR in 95% and 43% of the cell population, whereas normal monocytes (normal cells) only account for approximately 1%. Blocking the TfR by pretreatment with specific monoclonal antibodies reduces artemisinin sweet wormwood extract activity.

Apart from inducing apoptosis through selective oxidative stress mechanism. Artemisinin and its semisynthetic derivatives are also proven to be able to effectively induce cell growth arrest in cancer lines either by disrupting the cell cycle kinetics or by interfering with proliferation-interacting pathways. Every normal cells duplicates in an extensively regulated cell cycle, which is disregulated in cancer cells. Artemisinin-induced growth arrest has been reported at all cell cycle phases. Evidence of this acivity is proven in vitro so far in most cancer cells such as osteosarcoma, pancreas, leukemia and ovarian cancer.

According to series of scientific research by Life Science, sweet wormwood extract is proven to kill 98% of most lung cancers cells in less than 16 hours in vitro. Collectively, results demonstrate that the artemisinin impact on the E2F1 transcription factor mediates in stopping of the cell circuit of the breast cancer cells and it is a crucial transcription means in which the artemisinin controls the growth of the reproductive cancer cells. Researches state that because a breast cancer cell incorporates5 to 15 more receptors than regular cells, it absorbs iron more readily and therefore is more vulnerable to artemesinin's damage.

The ability of cancer cells to invade has been associated with high mortality and morbidity in cancer patients. The spread of cancer cells to other organs is a process in which cancer cells readily invade the surrounding tissue structure, reach and survive in the bloodstream, and finally seed at distant organs. An invaluable benefit of sweet wormwood extract, artemisinin is its relevant antimigratory activity in highly aggressive and invasive cancer cell lines.

After cancer cells succeed in their metastatic attempt, the next survival issue is to ensure conducive environment with increased supply of nutrients for proliferation. Cancer cells achieve this feat through an action known as angiogenesis. Blood vessels and stromal components are responsive to pro- and anti-angiogenic factors that allow vascular remodeling during development, wound healing and pregnancy. In situations such as cancer, however, the same angiogenic signaling pathways are induced and exploited. Several angiogenic activators including members of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) gene families and various inhibitors of angiogenesis have been described. In steady-state conditions, the balance between angiogenic activators and inhibitors results in very limited new blood vessel growth in the majority of tissues. Without new blood vessels to supply nutrients and dispose of catabolic products, tumor cells cannot sustain proliferation and thus are likely to remain dormant. Since survival and proliferation of cancer depends on angiogenesis, it is a target of cancer therapy. Sweet wormwoord extract, has been shown to inhibit the pro angiogenetic factors hindering the spread of cancer cells. Studies have so far evidenced the anti VEGF, FGF activity and other most commonly described angiogenetic factors by sweet wormwood derivatives.