Ascorbate and Tumor Cell Iron Metabolism: The Evolving Story and its Link to Pathology.

Vitamin C or ascorbate (Asc) is a water-soluble vitamin and antioxidant that is involved in many crucial biological functions. Asc's ability to reduce metals makes it an essential enzyme co-factor. Recent Advances: The ability of Asc to act as a reductant also plays an important part in its overall role in iron metabolism, where Asc induces both non-transferrin bound iron (NTBI) and transferrin-bound iron uptake at physiological concentrations (~ 50 µM). Moreover, Asc has emerged to play an important role in multiple diseases and its effects at pharmacological doses could be important for their treatment.Ascorbate's role as a regulator of cellular iron metabolism along with its cytotoxic effects and different roles at pharmacological concentrations makes it a candidate as an anti-cancer agent. Ever since the controversy regarding the studies from the Mayo Clinic were finally explained, there has been a renewed interest in using Asc as a therapeutic approach towards cancer due to its minimal side effects. Numerous studies have been able to demonstrate the anti-cancer activity of Asc through selective oxidative stress towards cancer cells via H2O2-generation at pharmacological concentrations. Studies have demonstrated that Asc's cytotoxic mechanism at concentrations (>1 mM) has been associated with decreased cellular iron uptake.Recent studies have also suggested other mechanisms, such as Asc's effects on autophagy, polyamine metabolism, the cell cycle, etc. Clearly, more has yet to be discovered about Asc's mechanism of action to facilitate safe and effective treatment options for cancer and other diseases.