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 IC(50) of 80 μM, whereas the electron transfer from CII to CIII was inhibited with IC(50) 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 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.
Highlights
Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs
We present data on the molecular mechanism of generation of reactive oxygen species (ROS) in cancer cells exposed to the novel vitamin E (VE) analog, MitoVE11S
We show that (i) MitoVE11S requires a functional CII for ROS generation and apoptosis induction; (ii) MitoVE11S very efficiently suppresses electron transfer from CII to CIII while only mildly inhibiting the succinate dehydrogenase (SDH) headgroup enzymatic activity of CII; (iii) the length of the hydrophobic chain of MitoVE11S is critical to allow the biologically active succinate moiety of the agent to reach the QP of CII; (iv) the UbQ-interacting Ser68 of the QP is important for the biological activity of MitoVE11S; and (v) the molecular mechanism by which MitoVE11S triggers apoptosis in cultured cells in vitro and suppresses tumor progression in vivo can be closely correlated to involve the CII QP binding and downstream effects
Summary
Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondria are emerging as targets for a variety of anti-cancer drugs [1,2,3,4,5] that belong to a group of compounds termed “mitocans” [6, 7] Of these agents, we and others have been studying the group of vitamin E (VE) analogs, epitomized by the “redox-silent” ␣-tocopheryl succinate (␣-TOS) and ␣-tocopheryl acetyl ether [8]. Of the several groups of mitocans, the anti-cancer VE analogs belong to both the class of BH3 mimetics, which includes compounds interfering with the interactions of the Bcl-2 family proteins [17], as well as to the class of agents that interfere with the mitochondrial electron redox chain The latter activity is probably the main reason for the strong apoptogenic efficacy of agents like ␣-TOS [18]. Our recent work documents that the prototypic compound of such a targeted VE analog (i.e. mitochondrially targeted vitamin E succinate (MitoVES)) is some 1–2 orders of magnitude more apoptogenic than the untargeted, parental compound
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