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

• Published in: Free radical biology & medicine Vol. 50; no. 11; pp. 1546 - 1555
• Main Authors: Dong, Lan-Feng, Jameson, Victoria J.A., Tilly, David, Prochazka, Lubomir, Rohlena, Jakub, Valis, Karel, Truksa, Jaroslav, Zobalova, Renata, Mahdavian, 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2011
• Subjects: alpha-tocopherol; Animals; Anti-cancer agents; anticarcinogenic activity; antineoplastic agents; Apoptosis; Apoptosis - drug effects; Drug Delivery Systems; Drug Therapy - trends; Free radicals; Humans; Jurkat Cells; Medicin och hälsovetenskap; mitochondria; Mitochondria - metabolism; Mitochondrial targeting; Models, Animal; Molecular Targeted Therapy; neoplasms; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; succinic acid; therapeutics; Tocopherols - chemistry; Tocopherols - pharmacology; transcription (genetics); Transcription, Genetic - drug effects; Triphenyl phosphonium; DHE; Reactive oxygen species; NS; UbQ; VES; EPR; α-TOS; ChIP; MitoQ; TPP; Triphenyl phosphonium; CII; Free radicals; DMPO; SOD; MOM; USI; BH3; MitoVES; VE; MIM; Mitochondrial targeting; ROS; TEM; Apoptosis
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.02.032

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.