Vitamin C and cancer revisited.

I n this issue of PNAS, Chen et al. (1) show that i.p. injection of ‘‘pharmacologic doses’’ of vitamin C decreases the growth and weight of human, rat, and murine tumor xenografts in athymic, nude mice. This work follows a number of articles by the same group, led by Mark Levine at the National Institute of Diabetes and Digestive and Kidney Diseases, showing that millimolar concentrations of extracellular vitamin C kill cancer cells but not normal cells in a hydrogen peroxide (H2O2)-dependent manner (1–3). Such millimolar concentrations of vitamin C can be achieved in humans by i.v. infusion but not by diet or supplements (4). Hence, vitamin C is postulated to exert local pro-oxidant effects in the interstitial f luid surrounding tumor cells, killing them or inhibiting their growth, while leaving normal cells intact (1–3). It is well known that vitamin C, or ascorbic acid, is an effective biologic antioxidant and does not act as a prooxidant under normal conditions (5) because it does not readily autoxidize, i.e., react with oxygen (O2) to produce reactive oxygen species, such as superoxide radicals (O2 ● ) or H2O2. However, ascorbate readily donates an electron to redox-active transition metal ions, such as cupric (Cu2 ) or ferric (Fe3 ) ions, reducing them to cuprous (Cu ) and ferrous (Fe2 ) ions, respectively (Reaction 1). In fact, reduction of copper or iron in the catalytic site of certain enzymes underlies ascorbate’s well known biologic function as a co-substrate in procollagen, carnitine, and catecholamine biosynthesis (6). Reduced transition metal ions, in contrast to ascorbic acid, readily react with O2, reducing it to superoxide radicals (Reaction 2), which in turn dismutate to form H2O2 and O2 (Reaction 3):