A Novel Anticancer Stem Cell Compound Derived from Pleuromutilin Induced Necroptosis of Melanoma Cells

Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.坏死性凋亡（Necroptosis）是近年被证实的一类非凋亡型程序性细胞死亡方式。开发能够诱导癌细胞发生坏死性凋亡的新型化学实体，有望成为临床应对药物耐药性的替代治疗策略。本研究报道了一种新型截短侧耳素（Pleuromutilin）衍生物（化合物38），该化合物可显著提升细胞内活性氧（Reactive Oxygen Species, ROS）水平，并通过坏死性凋亡途径诱导黑色素瘤癌细胞死亡。此外，化合物38可显著清除多种癌症干细胞，并在体外与体内实验中均能抑制黑色素瘤癌细胞的增殖。不仅如此，该化合物在动物模型中展现出低毒性与优异的药代动力学（PK）性质，目前正作为潜在抗癌候选药物开展验证研究。