Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II
Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial Complex II
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DOI：
10.1074/jbc.m110.186643
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发表时间：
2011-02-04
影响因子：
4.8
通讯作者：
Neuzil, Jiri
中科院分区：
文献类型：
--
作者：
Dong, Lan-Feng;Jameson, Victoria J. A.;Neuzil, Jiri
线粒体复合物II（CII）是近年来发现的一种新型抗癌药物靶点。线粒体靶向维生素E琥珀酸酯（MitoVES）经过修饰，使其优先定位于线粒体，大大增强了其促凋亡和抗癌活性。使用基因操作的细胞，MitoVES引起细胞凋亡和活性氧（ROS）的产生，在CII-熟练的恶性细胞，但不是他们的CII功能障碍的同行。MitoVES抑制CII的琥珀酸脱氢酶（SDH）活性，IC 50为80 μ M，而从CII到CIII的电子转移被抑制，IC 50为1.5 μ M。该试剂对CI的酶活性或从CI到CIII的电子转移没有影响。在24小时内，MitoVES引起与GFP融合的HIF 1 α的氧依赖性破坏结构域的稳定，表明促进了假缺氧状态。分子建模预测琥珀酰基锚定到近端CII泛醌（UbQ）结合位点，并连续降低相互作用能量的连续较短的植基链同系物的MitoVES与其较低的影响，细胞凋亡诱导，ROS的产生，和SDH活性。CII SDHC亚基近端位点（S68 A或S68 L）内UbQ结合Ser（68）的突变抑制了ROS生成和MitoVES诱导的细胞凋亡。体内研究表明，MitoVES还通过在肿瘤抑制的背景下引起假性缺氧而起作用。我们提出，具有11个碳链的VES的线粒体靶向将该试剂定位于线粒体内膜和基质界面的理想位置，优化其作为抗癌药物的生物学效应。
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 mu M, whereas the electron transfer from CII to CIII was inhibited with IC50 of 1.5 mu M. 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 HIF1 alpha 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 Ser(68) 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.