Artemisinins are antimalarial drugs isolated from the plant Artemisia annua, which have been used as therapeutics for malaria and fevers in Chinese medicine for thousands of years. In modern times artemisinins are used for the treatment of malaria as recommended by the WHO since its discovery in the late 1970’s. Artemisinins are thought to kill the malaria parasite by generating an excess of free radicals to induce oxidative stress, and they exhibit remarkably little toxicity to patients.
Of interest to us, artesunate, a derivative of artemisinin, is undergoing early testing for use in the treatment of various cancers. Artesunate has been shown to kill diverse types of cancer cells in vitro and was able to cause regression of some tumours in mouse models. Excitingly, artesunate is undergoing Phase I clinical trials for the treatment of late stage colorectal cancer, breast cancer and hepatocellular carcinoma.
While the mechanism by which artesunate kills cancer cells is still debated, there is growing evidence to show that cells treated with aresunate die by apoptosis - a fundamental cell death process by which multicellular organisms maintain tissue homeostasis. Evasion of apoptosis is a hallmark of cancer and a cause of resistance of malignant cells to diverse chemotherapeutics. Excitingly, a new class of drugs (termed BH3 mimetics) have been developed to activate the apoptotic machinery directly to kill cancer cells[4,5].
Using the human multiple myeloma (MM) derived cell-line RPMI8226, we could show that artesunate kills by inducing apoptosis, as cells are completely resistant to artesunate in the absence of the essential apoptosis effector proteins BAK and BAX. Furthermore, artesunate synergised potently with the BH3 mimetic ABT-737 to kill MM cells. We now aim to identify the essential apoptosis initiators for artesunate-induced killing by performing a targeted CRISPR/CAS9 screen against all pro-apoptotic BH3-only proteins. Additionally, we will expand the range of cell lines studied, to test whether the apoptosis induction caused by artesunate occurs in different cancer cell types. Artesunate and the BH3 mimetic Venetoclax (ABT-737 analogue) are both approved for human use. Hence combination therapies could be rapidly translated into the clinic to improve patient outcomes.