Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 15, Issue 12, Pages 2923-2935Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2011.4192
Keywords
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Funding
- Australian Research Council
- National Health and Medical Research Council of Australia
- Cancer Council Queensland
- Grant Agency of the Czech Republic [204/08/0811, 305/07/1008, P301/10/1937]
- Grant Agency of the Academy of Sciences of the Czech Republic [KAN200520703]
- National Institutes of Health [NS42617, GM77185, GM69589]
- Ministry of Education, Youth and Sports of the Czech Republic [1M6837805002]
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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 alpha-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 alpha-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. Antioxid. Redox Signal. 15, 2923-2935.
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