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

被引：111

作者：

Dong, Lan-Feng ^{[5
]}

Jameson, Victoria J. A. ^{[1
]}

Tilly, David ^{[2
]}

Prochazka, Lubomir ^{[3
]}

Rohlena, Jakub ^{[4
]}

Valis, Karel ^{[4
]}

Truksa, Jaroslav ^{[4
]}

Zobalova, Renata ^{[4
,5
]}

Mandavian, Elahe ^{[6
]}

Kluckova, Katarina ^{[4
]}

Stantic, Marina ^{[5
]}

Stursa, Jan ^{[7
]}

Freeman, Ruth ^{[5
]}

Witting, Paul K. ^{[8
]}

Norberg, Erik ^{[9
]}

Goodwin, Jacob ^{[5
]}

Salvatore, Brian A. ^{[6
]}

Novotna, Jana ^{[4
]}

Turanek, Jaroslav ^{[3
]}

Ledvina, Miroslav ^{[7
]}

Hozak, Pavel ^{[10
]}

Zhivotovsky, Boris ^{[9
]}

Coster, Mark J. ^{[2
]}

Ralph, Stephen J. ^{[5
]}

Smith, Robin A. J. ^{[1
]}

Neuzil, Jiri ^{[4
,5
]}

机构：

[1] Univ Otago, Dept Chem, Dunedin, New Zealand

[2] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Nathan, Qld 4111, Australia

[3] Vet Res Inst, CS-62132 Brno, Czech Republic

[4] Acad Sci Czech Republ, Inst Biotechnol, Prague, Czech Republic

[5] Griffith Univ, Sch Med Sci, Southport, Qld 4222, Australia

[6] Louisiana State Univ, Dept Chem & Phys, Shreveport, LA 71115 USA

[7] Acad Sci Czech Republ, Inst Biochem & Organ Chem, Prague, Czech Republic

[8] Univ Sydney, Sydney Med Sch, Bosch Res Inst, Discipline Pathol, Sydney, NSW 2006, Australia

[9] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[10] Acad Sci Czech Republ, Inst Mol Genet, Prague, Czech Republic

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2011年 / 50卷 / 11期

基金：

澳大利亚研究理事会; 瑞典研究理事会;

关键词：

Mitochondrial targeting; Triphenyl phosphonium; Reactive oxygen species; Apoptosis; Anti-cancer agents; Free radicals; VITAMIN-E SUCCINATE; E ANALOGS; TUMOR-CELLS; IN-VIVO; ANTIOXIDANT; INDUCTION; GROWTH; BCL-2; BAK; MESOTHELIOMA;

D O I：

10.1016/j.freeradbiomed.2011.02.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：1546 / 1555

页数：10

共 55 条

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