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.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.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.
