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

¹ Apoptosis Research Group and ² Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia; ³ Microbiology and Immunology, University of Arizona, Tucson, Arizona; ⁴ Veterinary Research Institute, Brno, Czech Republic; ⁵ ANZAC Research Institute, Concord Hospital, University of Sydney, Concord, New South Wales, Australia; and ⁶ Molecular Therapy Group, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic

Requests for reprints: Jiri Neuzil, Apoptosis Research Group, Heart Foundation Research Centre, School of Medical Science and the Griffith Institute of Health and Medical Research, Griffith University, Southport 9716, Queensland, Australia. Phone: 61-2-555-29109; Fax: 61-2-555-28444; E-mail: j.neuzil{at}griffith.edu.au.

"Mitocans" from the vitamin E group of selective anticancer drugs, -tocopheryl succinate (-TOS) and its ether analogue -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 "wound-healing" 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. -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]