Vitamin C and cell death.

SIGNIFICANCE Persistent oxidative stress is a common feature of cancer cells, giving a specific weapon to selectively eliminate them. Ascorbate in pharmacologic concentration can contribute to the suspended formation of hydroxyl radical via the Fenton reaction, thus it can be an important element of the oxidative stress therapy against cancer cells. Recent Advances: The main components of ascorbate induced cell death are DNA double-strand breaks via the production of hydroxyl radical and ATP depletion due to the activation of PARP1. Presumably, DNA damage can be the primary contributor to the anti-cancer activity of pharmacologic ascorbate, as opposed to the rupture of bioenergetics. The caspase independency of high dose ascorbate induced cell death proposed the possible involvement of several types of cell death such as ferroptosis, necroptosis and autophagy. CRITICAL ISSUES Ascorbate can target at least two key molecular features of cancer cells as a part of the anti-cancer therapy: the intrinsic or acquired resistance to cell death and the dysregulated metabolism of cancer cells. It seems probable that different concentrations of ascorbate alter the nature of induced cell death. Autophagy and necroptosis may play a role at intermediate concentrations, but caspase independent apoptosis may dominate at higher concentrations. However, ascorbate behaves as an effective inhibitor of ferroptosis that may have crucial importance in its possible clinical application. FUTURE DIRECTIONS The elucidation of the details and the links between high dose ascorbate induced cancer selective cell death mechanisms may give us a tool to form and apply synergistic cancer therapies.