Exploring the impact of high-dose vitamin C in cancer therapy: the role of reactive oxygen species, TETs and potential combination therapies

Vitamin C, or ascorbic acid, is an essential micronutrient for human and other primates. Ascorbate molecule can be found in different redox forms based on the biological conditions. Ascorbate is the fully reduced form, while dehydroascorbic acid (DHA) is the fully oxidized form of vitamin C, which can easily enter the cells through glucose transporter-1 (GLUT1) for its similarity to glucose. The potential anti-cancer activity of high-dose intravenous vitamin C was first proposed in 1976 by Cameron and Pauling. This original finding led to several investigations on vitamin C pharmacokinetics and on its possible use in cancer therapy. Remarkably, different mechanisms of action have been proposed to define the antitumoral potential of vitamin C, as its ability to module redox balance and the activity of specific enzymes involved in cancer biology. To better understand the role of ascorbate, it is also necessary to consider the metabolic alterations typical of cancer cells, as the presence of high-level labile iron pools that are subjected to the vitamin C electron donor ability, a condition that strongly promotes ROS production. Notably, ascorbate acts as a cofactor of critical epigenetic modifiers of TET family members, like TET2, that are frequently deregulated in leukemia. Thereby, vitamin C has been proposed to restore TET2 partial deficiency in leukemia, alone or in combination with PARP inhibitors, while the association of fasting-mimicking diet (FMD) with ascorbate seems particularly effective on KRAS mutated cancers, also in a triple regimen with chemotherapy. In this context, FMD sensitizes KRAS-mutant tumors to vitamin C treatment by modulating heme-oxygenase-1 expression and thus influencing the ferritin/iron pathway and ROS production. Finally, in non-small cell lung cancer and glioblastoma, vitamin C treatment increases labile iron pool levels and consequently promotes mitochondrial O2•- and H2O2 production, thus contributing to cancer cell killing, especially when used in combination with radio-chemotherapy. In summary, significant reports suggest vitamin C as a low cost, but effective anticancer therapeutic drug, in particular when used in combination regimens.