The Role of Oxidative Stress Induction of Apoptosis in Proliferating Endothelial Cells: Vitamin E Analogues Inhibit Angiogenesis by Selective

‘‘Mitocans’’ from the vitamin E group of selective anticancer drugs, A-tocopheryl succinate (A-TOS) and its ether analogue A-TEA, triggered apoptosis in proliferating but not arrested endothelial cells. Angiogenic endothelial cells exposed to the vitamin E analogues, unlike their arrested counterparts, readily accumulated reactive oxygen species (ROS) by interfering with the mitochondrial redox chain and activating the intrinsic apoptotic pathway. The vitamin E analogues inhibited angiogenesis in vitro as assessed using the ‘‘woundhealing’’ and ‘‘tube-forming’’ models. Endothelial cells deficient in mitochondrial DNA (mtDNA) were resistant to the vitamin E analogues, both in ROS accumulation and apoptosis induction, maintaining their angiogenic potential. A-TOS inhibited angiogenesis in a mouse cancer model, as documented by ultrasound imaging. We conclude that vitamin E analogues selectively kill angiogenic endothelial cells, suppressing tumor growth, which has intriguing clinical implications. [Cancer Res 2007;67(24):11906–13]