Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2
Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2
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DOI：
10.1007/s10495-011-0625-x
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发表时间：
2011-10-01
期刊：
影响因子：
7.2
通讯作者：
Lemaire, Christophe
中科院分区：
文献类型：
--
作者：
Mayola, Eleonore;Gallerne, Cindy;Lemaire, Christophe
恶性皮肤黑色素瘤是最具侵袭性和致命性的皮肤癌，对常规抗癌化疗具有高耐药性和异质性反应。Withaferin A（WFA）是一种来源于药用植物睡茄的睡茄素，据报道其对多种癌细胞具有抗肿瘤活性。我们首次研究了WFA对一组四种不同的人黑色素瘤细胞的死亡诱导潜力，并研究了所涉及的细胞机制。WFA诱导凋亡性细胞死亡，IC 50范围为1.8 - 6.1 μ M。细胞对WFA诱导的凋亡的敏感性与低Bcl-2/Bax和Bcl-2/Bim比率相关。在所有细胞系中，由WFA触发的凋亡过程涉及线粒体途径，并且与Bcl-2下调、Bax线粒体易位、细胞色素c释放到胞质溶胶中、跨膜电位（Delta Psi m）耗散、半胱天冬酶9和半胱天冬酶3激活以及DNA片段化相关。WFA细胞毒性需要早期活性氧（ROS）产生和谷胱甘肽耗竭，抗氧化剂N-乙酰半胱氨酸对ROS增加的抑制导致线粒体和核事件的完全抑制。总之，这些结果支持WFA对人黑色素瘤的治疗潜力。
A high resistance and heterogeneous response to conventional anti-cancer chemotherapies characterize malignant cutaneous melanoma, the most aggressive and deadly form of skin cancer. Withaferin A (WFA), a withanolide derived from the medicinal plant Withania somnifera, has been reported for its anti-tumorigenic activity against various cancer cells. For the first time, we examined the death-inducing potential of WFA against a panel of four different human melanoma cells and investigated the cellular mechanisms involved. WFA induces apoptotic cell death with various IC50 ranging from 1.8 to 6.1 mu M. The susceptibility of cells toward WFA-induced apoptosis correlated with low Bcl-2/Bax and Bcl-2/Bim ratios. In all cell lines, the apoptotic process triggered by WFA involves the mitochondrial pathway and was associated with Bcl-2 down regulation, Bax mitochondrial translocation, cytochrome c release into the cytosol, transmembrane potential (Delta Psi m) dissipation, caspase 9 and caspase 3 activation and DNA fragmentation. WFA cytotoxicity requires early reactive oxygen species (ROS) production and glutathione depletion, the inhibition of ROS increase by the antioxidant N-acetylcysteine resulting in complete suppression of mitochondrial and nuclear events. Altogether, these results support the therapeutic potential of WFA against human melanoma.