Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate, an agent with antineoplastic activity:: Comparison with receptor-mediated pro-apoptotic signaling
Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate, an agent with antineoplastic activity:: Comparison with receptor-mediated pro-apoptotic signaling
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DOI：
10.1021/bi020527j
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发表时间：
2003-04-15
期刊：
影响因子：
2.9
通讯作者：
Neuzil, J
中科院分区：
文献类型：
--
作者：
Weber, T;Dalen, H;Neuzil, J
α-生育酚琥珀酸酯（α-TOS）是具有高促细胞凋亡和抗肿瘤活性的半合成维生素E类似物[Weber，T等（2002）Clin. Cancer Res.8，863-869]。以前的研究表明，它通过破坏亚细胞细胞器（包括线粒体）的稳定来发挥作用，但缺乏令人信服的证据。用α-TOS处理的细胞显示改变的线粒体结构、自由基的产生、鞘磷脂循环的激活、细胞色素c和Smac/Diablo的重新定位以及多种半胱天冬酶的激活。泛半胱天冬酶抑制剂抑制半胱天冬酶-3和-6活化和磷脂酰丝氨酸外化，但不降低线粒体膜电位或自由基的产生。对于α-TOS，而不是Fas或TRAIL，凋亡被caspase-9抑制抑制，而过表达cFLIP或CrmA的TRAIL和Fas抗性细胞对α-TOS敏感。线粒体的核心作用被证实的线粒体DNA缺陷细胞的耐药性α-TOS，通过调节α-TOS细胞凋亡的Bcl-2家族成员，并通过抗凋亡活性的神经靶向自由基清除剂。用α-TOS和抗Fas IgM的共处理显示了它们的协同作用，可能是通过经由不同的会聚途径的信号传导。这些数据提供了对alpha-TOS杀死恶性细胞的分子机制的深入了解，并主张将其作为潜在的抗癌剂或佐剂进行测试。
alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with alpha-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For alpha-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to alpha-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to alpha-TOS, by regulation of alpha-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with alpha-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which alpha-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.