AIMS: A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of α-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. RESULTS: MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorter-chain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. INNOVATION AND CONCLUSION: We conclude that MitoVES, a mitochondrially targeted analog of α-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing.

• MeSH
• alpha-Tocopherol analogs & derivatives   pharmacology   therapeutic use   MeSH
• Apoptosis drug effects   MeSH
• Cell Line MeSH
• Endothelial Cells drug effects   MeSH
• Wound Healing drug effects   MeSH
• Angiogenesis Inhibitors chemistry   pharmacology   therapeutic use   MeSH
• Humans MeSH
• DNA, Mitochondrial metabolism   MeSH
• Mitochondria drug effects   MeSH
• Disease Models, Animal MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neoplasms blood supply   drug therapy   MeSH
• Neovascularization, Pathologic drug therapy   MeSH
• Cell Proliferation drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• alpha-Tocopherol MeSH
• Angiogenesis Inhibitors MeSH
• DNA, Mitochondrial MeSH