The physiological functions of ascorbate in the development of cancer

Abstract

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.

Fig. 1.

Physiological and pharmacological ascorbate plasma concentrations in humans and their proposed mechanisms of action in cancer modulation. Supraphysiological concentrations achieved through IV administration elevate ROS and kill cancer cells preferentially over normal cells via mechanisms that remain unclear. High physiological ascorbate concentrations achieved through diet or oral supplementation stimulate activity of TET leukemia suppressor enzymes in hematopoietic cells. Ascorbate deficiency leads to TET deficiency and promotes leukemia development. The cell types targeted by ascorbate and whether there are additional molecular mechanisms of action in most cancers remain unclear. IP, intraperitoneal; IV, intravenous; ROS, reactive oxygen species; TET, ten-eleven translocation.