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

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Title Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy
Author Dong, Lan-feng; Jameson, Victoria J.A.; Tilly, David Patrice; 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 John; Smith, Robin A.J.; Neuzil, Jiri
Journal Name Free Radical Biology & Medicine
Year Published 2011
Place of publication United States
Publisher Elsevier
Abstract 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1016/j.freeradbiomed.2011.02.032
Volume 50
Issue Number 11
Page from 1546
Page to 1555
ISSN 0891-5849
Date Accessioned 2012-02-28; 2012-03-01T22:15:37Z
Research Centre Eskitis Institute for Drug Discovery; Griffith Health Institute; Molecular Basis of Disease
Faculty Griffith Health Faculty
Subject Biochemistry and Cell Biology
URI http://hdl.handle.net/10072/43236
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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