Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II

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Title Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II
Author Dong, Lan-feng; Jameson, Victoria J. A.; Tilly, David Patrice; Cerny, Jiri; Mahdavian, Elahe; Marín-Hernandez, Alvaro; Hernandez-Esquivel, Luz; Rodríguez-Enríquez, Sara; Stursa, Jan; Witting, Paul K.; Stantic, Bela; Rohlena, Jakub; Truksa, Jaroslav; Kluckova, Katarina; Dyason, Jeffrey Clifford; Ledvina, Miroslav; Salvatore, Brian A.; Moreno-Sanchez, Rafael; Coster, Mark J.; Ralph, Stephen John; Smith, Robin A. J.; Neuzil, Jiri
Journal Name Journal of Biological Chemistry
Editor Martha Fedor
Year Published 2011
Place of publication United States
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Abstract Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC50 of 80 μm, whereas the electron transfer from CII to CIII was inhibited with IC50 of 1.5 μm. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1α fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1074/jbc.M110.186643
Copyright Statement This research was originally published in Journal of Biological Chemistry (JBC). Lan-Feng Dong etc, Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II, Journal of Biological Chemistry (JBC), 2011; Vol. 286(5), pp. 3717-3728. Copyright the American Society for Biochemistry and Molecular Biology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitve version.
Volume 286
Issue Number 5
Page from 3717
Page to 3728
ISSN 0021-9258
Date Accessioned 2011-01-31
Date Available 2011-10-19T07:26:27Z
Language en_AU
Research Centre Eskitis Institute for Drug Discovery; Griffith Health Institute; Institute for Integrated and Intelligent Systems; Molecular Basis of Disease
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Medical Microbiology
URI http://hdl.handle.net/10072/39853
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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