Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern
chemotherapy schemes, new
radiotherapy techniques, targeted
therapies and
immunotherapy has brought new hope in the treatment of these diseases. Unfortunately,
cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (
ascorbic acid or
vitamin C) is a potent water-soluble
antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack
enzymes for its synthesis. Ascorbate has
antioxidant effects that correspond closely to the dose administered. Interestingly, this natural
antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with
iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with
ischemia-reperfusion. This effect could be positively modulated by the interaction of
iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in
cancer therapies such as
radiotherapy, radio-
chemotherapy,
chemotherapy,
immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of
reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of
cancer to achieve their application in human medicine.