Artemisinin, the magic remedy discovered in traditional Chinese medicine.

Artemisinin therapy is characterized by its excellent tolerability and relative accessibility. This combination of proven safety and affordability makes artemisinin a drug of exceptional interest for reuse studies. In fact, interest in non-malarial applications of artemisinin has steadily increased over time since artemisinin was first released in the world. Although malaria remains the only disease for which artemisinin is an approved treatment, the potential applications of artemisinin in anti-cancer, anti-inflammatory, anti-parasitic (not malaria) and anti-viral functions, among others, have been seriously explored. over the years. Here, we briefly comment on some promising research on the reuse of artemisinin, especially in the field of cancer treatment, as a window for future drug development.

The efficacy of artemisinin in cancer cultures was first reported in 1993 and has since been expanded and broadly characterized. It is now well reported that artemisinin and its derivatives exhibit selective cytotoxicity against a variety of cancer types in in vitro and in vivo studies. The forays into clinical trials have generally been promising, although limited in number and scale. More than two decades of research based on the action of artemisinin in cancer have uncovered a multitude of targets and implicated mechanisms. Artemisinin has been reported to induce mitochondrial apoptosis and other forms of cell death such as necroptosis, inhibit angiogenesis and cancer metastasis, and interrupt the cancer cell cycle. These results are mediated by a combination of oxidative damage, DNA damage, altered gene expression, and interactions with a wide range of signaling pathways, including the mammalian target of rapamycin (mTOR), NF-κB, mitogen-activated protein ( MAP) kinases and Wnt / β-catenin, among many others. These pathways and mechanisms have been extensively reviewed in recent publications.

While pathway validation is an important aspect of the mechanistic study, it is also necessary to consider the big picture in terms of unifying drug activation and downstream activity in a similar way to what has been done in the malaria studies. As in the case of malaria parasites, it is likely that the activation mechanism of artemisinin in cancer cells is strongly linked to its specificity of action. Thus, the role of free ferrous iron versus free redox active heme is once again being examined, especially considering that iron is closely linked to artemisinin-induced cytotoxicity in cancer. Recent studies have once again shed light on the role of heme in activating artemisinin in cancer cells, drawing parallels with the case of malaria. In particular, a variety of methodologies were used to demonstrate that modulation of heme synthesis and availability clearly correlates with cytotoxicity. It is also important to note that cancer cells have been reported to have increased levels of metabolism and heme synthesis, and that this could support artemisinin's cancer specificity in a similar way to the case of malaria. Specific targeting of artemisinin to mitochondria (the site of heme synthesis in mammalian cells) or increasing heme levels by treatment with heme-precursor aminolevulinic acid (ALA) improved anticancer activity. A heme-centered activation mechanism and an iron-dependent cytotoxicity mechanism could be a point of reconciliation between the roles of these two species in the anticancer activity of artemisinin. Further work to fully understand the basis for the specificity of artemisinin in cancer will be critical for future therapeutic applications.

At the same time, it is necessary to consider the appropriate direction when moving forward in terms of validation of artemisinin MOAs in cancer. Consider the case of malaria, where artemisinin is proposed to indiscriminately attack adjacent targets after activation. If artemisinin is similarly activated in cancer cells, it is plausible that the same promiscuous multi-target mechanism occurs. This would explain the remarkable range of cellular effects and implicated pathways that have already been reported, since multiple targets and functional pathways are likely to be affected simultaneously by such a mechanism. In fact, recent unbiased studies of artemisinin cancer targets using proteomic approaches have revealed a similar multi-target MOA by artemisinin in cancer cells. The cytotoxicity mechanism itself is also a matter of great interest, especially with regard to non-apoptotic forms of cell death. Recent work has closely linked artemisinin-induced cytotoxicity to oxidative

This work was supported, in whole or in part, by the projects of the National Natural Science Foundation of China (81641002 and 81473548); China's Leading National Science and Technology Program for Innovative Medicines (2017ZX09101002-001-001-05 and 2017ZX09101002-001-001-3); and the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ10-024 and ZXKT18003). We would like to thank Dr. Lina Chen, Li Xiang and Yuhua Shi for providing Artemisia annua L's photo. Sanjeev Krishna and Prof. Svetlana Tsogoeva for her valuable comments and assistance in polishing our manuscript.

Compliance with ethical guidelines: Jigang Wang, Chengchao Xu, Yin Kwan Wong, Yujie Li, Fulong Liao, Tingliang Jiang and Youyou Tu declare that they have no conflicts of interest or financial conflicts to disclose.