The physiological functions of ascorbate in the development of cancer.

The metabolite ascorbate (vitamin C) is synthesized endogenously in most animals or, in humans and some other species, obtained from the diet. Its role in cancer development is controversial. Addition of ascorbate to cultured cells or high-dose administration in animals can inhibit growth of many cancers, but most of these effects are caused by non-physiological biochemical activities. Few experiments have tested the physiological roles of ascorbate in cancer development by depleting it in physiological settings. Ascorbate depletion inhibits the activity of ten-eleven translocation (TET) enzymes in hematopoietic and leukemia cells and accelerates myeloid leukemia development. Many clinical trials have tested ascorbate supplementation in cancers and shown little or no evidence that it has a beneficial role. I propose that depletion experiments are needed to define the cancers in which ascorbate has a physiological role, establish its cellular and molecular targets, and provide a rationale for clinical trials.