Mitochondria are emerging as intriguing targets for anti-cancer agents.Vitamin E succinate (VES) has been shown to efficiently kill different types of cancer cells.A mitochondrially targeted analogue of VES (MitoVES), modified by tagging the parental compound with the triphenylphosphonium (TPP) group, 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.Mitochondrial complex Ⅱ (CⅡ) has been recently identified as a novel target for anti-cancer drugs.MitoVES is modified so that it is preferentially localised to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity, as well as the anti-angiogenic activity.MitoVES was found to efficiently suppress angiogenesis in vitro by inducing accumulation of reactive oxygen species (ROS) and induction of apoptosis in proliferating/angiogenic Ecs but not arrested Ecs.This is at least partially due to the lower mitochondrial inner trans-membrane potential in arrested Ecs com-pared to the proliferating cells, which results in the lower level of mitochondrial uptake of MitoVES.Using genetically manipulated cells, MitoVES caused apoptosis and generation of 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 exerted no effect either on the enzymatic activity of CI or on electron transfer from CⅠ to CⅢ.Molecular modelling predicted the succinyl group anchored into the proximal CⅡ ubiquinone (UbQ)-binding site (Qp), and successively reduced interaction energy for serially shorter phytyl chain homologues of MitoVES correlated with their lower effects on apoptosis induction, ROS generation and SDH activity.Mutation of the UbQbinding S68 within the Qp of the CⅡ SDHC subunit suppressed both ROS generation and apoptosis induction by MitoVES.In vivo studies indicated that MitoVES also significant suppresses tumour progress and the associated angiogenesis.We propose that mitochondrial targeting of VES maximises its anti-cancer drug, endowing it with a substantial translational spin.