title: Mitochondrially targeted α-tocopheryl succinate is antiangiogenic: potential benefit against tumor angiogenesis but caution against wound healing.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. jakub.rohlena@img.cas.cz
authors: Jakub
authors: J
authors: Rohlena
authors: Lan-Feng
authors: LF
authors: Dong
authors: Katarina
authors: K
authors: Kluckova
authors: Renata
authors: R
authors: Zobalova
authors: Jacob
authors: J
authors: Goodwin
authors: David
authors: D
authors: Tilly
authors: Jan
authors: J
authors: Stursa
authors: Alena
authors: A
authors: Pecinova
authors: Anatoly
authors: A
authors: Philimonenko
authors: Pavel
authors: P
authors: Hozak
authors: Jaideep
authors: J
authors: Banerjee
authors: Miroslav
authors: M
authors: Ledvina
authors: Chandan K
authors: CK
authors: Sen
authors: Josef
authors: J
authors: Houstek
authors: Mark J
authors: MJ
authors: Coster
authors: Jiri
authors: J
authors: Neuzil
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014945:Wound Healing / Q000187:drug effects*; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D004272:DNA, Mitochondrial; D024502:alpha-Tocopherol