Mitochondrial targeting of alpha-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy

作者：Dong Lan Feng^*; Jameson Victoria J A; Tilly David; Prochazka Lubomir; Rohlena Jakub; Valis Karel; Truksa Jaroslav; Zobalova Renata; Mandavian Elahe; Kluckova Katarina; Stantic Marina; Stursa Jan; Freeman Ruth; Witting Paul K; Norberg Erik; Goodwin Jacob; Salvatore Brian A; Novotna Jana; Turanek Jaroslav; Ledvina Miroslav; Hozak Pavel; Zhivotovsky Boris; Coster Mark J; Ralph Stephen J; Smith Robin A J; Neuzil Jiri

来源：Free Radical Biology and Medicine, 2011, 50(11): 1546-1555.

DOI：10.1016/j.freeradbiomed.2011.02.032

• Mitochondrial targeting
• Triphenyl phosphonium
• Reactive oxygen species
• Apoptosis, Anti-cancer agents
• Free radicals

Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested here a novel approach, whereby the mitochondrially targeted delivery of anti-cancer drugs is enhanced by the addition of a triphenylphosphonium group (TPP(+)). A mitochondrially targeted analog of vitamin E succinate (MitoVES), modified by tagging the parental compound with TPP+, induced considerably more robust apoptosis in cancer cells with a 1-2 log gain in anti-cancer activity compared to the unmodified counterpart, while maintaining selectivity for malignant cells. This is because MitoVES associates with mitochondria and causes fast generation of reactive oxygen species that then trigger mitochondria-dependent apoptosis, involving transcriptional modulation of the Bcl-2 family proteins. MitoVES proved superior in suppression of experimental tumors compared to the untargeted analog. We propose that mitochondrially targeted delivery of anti-cancer agents offers a new paradigm for increasing the efficacy of compounds with anti-cancer activity.

• 出版日期2011-6-1