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

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 genetica...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of biological chemistry Vol. 286; no. 5; pp. 3717 - 3728
Main Authors Dong, Lan-Feng, Jameson, Victoria J.A., Tilly, David, Cerny, Jiri, Mahdavian, Elahe, Marín-Hernández, Alvaro, Hernández-Esquivel, Luz, Rodríguez-Enríquez, Sara, Stursa, Jan, Witting, Paul K., Stantic, Bela, Rohlena, Jakub, Truksa, Jaroslav, Kluckova, Katarina, Dyason, Jeffrey C., Ledvina, Miroslav, Salvatore, Brian A., Moreno-Sánchez, Rafael, Coster, Mark J., Ralph, Stephen J., Smith, Robin A.J., Neuzil, Jiri
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 04.02.2011
American Society for Biochemistry and Molecular Biology
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.186643