Abstract
The down regulation of the cellular power generator, adenosine triphosphate (ATP) synthase, in various cancer cells plays an obstructive role in mitochondria-mediated cell death. Cancer cells up-regulate ATPase inhibitory factor 1 (IF1) and down-regulate β-F
-ATPase of ATP synthase to enhance aerobic glycolysis for tumor growth
inhibiting total ATP synthase activity in the oxidative phosphorylation (OXPHOS) pathway. Alpha-tocopheryl succinate (α-TOS), one of the most bioactive derivatives of vitamin E, can selectively induce apoptosis in numerous cancer cells. The cancer cell selective apoptosis inducing property of α-TOS is correlated to: mitochondrial destabilization, inhibition of anti-apoptotic B cell lymphoma 2 (Bcl2) and protein kinase C (PKC), caspase 3 activation, production of mitochondrial reactive oxygen species (ROS), and inhibition of succinate dehydrogenase activity of mitochondrial complex II, and interaction with complex I to some extent. There is no report which elucidates the effects of α-TOS on the cellular power generator, complex V or ATP synthase. Here, we report the activation of mitochondrial ATP synthase using a suitably designed chemical formulation of α-TOS for the first time. A mitochondria targeted α-TOS nanoparticle formulation demonstrated enhanced cytotoxicity and mitochondrial activities in cancer cells by inhibiting Bcl2 protein and activating ATP synthase. The modulation of ATP synthase in cancer cells by the engineered formulation of α-TOS can be promising for solid cancers with compromised ATP synthase.
