Abstract
Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity.
Highlights
Chinese herb Artemisia annua L., has profound activity against malaria.[1]
The low grade tumours caused by Neurofibromatosis 2 (NF2) gene mutations do not respond well to current cancer drugs and therapy is restricted to surgery and radiosurgery.[26]
ART has been well documented in drug safety and efficacy in anti-malarial therapy, and it has been attractive as a cancer drug candidate due to its selective toxicity to cancer cells and low toxicity to normal cells
Summary
Chinese herb Artemisia annua L., has profound activity against malaria.[1]. Artemisinin contains an endoperoxide moiety that reacts with iron to produce toxic reactive oxygen species (ROS). The pharmacokinetics and tolerance of ART as an anti-malarial drug have been well documented, with clinical studies showing excellent safety. These properties make artemisinin-based compounds attractive drug candidates for cancer chemotherapy. The RIP1-RIP3 complex highlights the signals that regulate necroptosis.[15,16,17] Artemisinin derivatives, mostly ART, have been suggested to lead to apoptosis via ROS production in cancer cells. Artemisinin or its analogues were shown to inhibit cell proliferation in multiple cancer cells by regulating cell-cycle arrest[21,22,23] or inducing apoptosis.[24,25] the detailed molecular mechanisms underlying artemisinin or ART-induced cell death are poorly understood, need to be further addressed.
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