Vitamin C in cancer.

Abstract

Vitamin C is a necessary nutrient for humans because we are unable to synthesize it. Most animals synthesize vitamin C in the liver from glucose, but humans have lost the gene encoding the last enzyme in a chain required for vitamin C synthesis. Other primates, the guinea pig, the fruit-eating bat, certain salmon and trout, and some grasshoppers are in the same predicament. How and why this came about during evolution is uncertain, but the result of not ingesting sufficient vitamin C in the diet is scurvy and, ultimately, death. Vitamin C is a critical antioxidant in the body and is an essential cofactor for various enzymes. The evolving understanding of the role of redox in cell signaling, apoptosis, DNA damage, and other vital functions indicates that vitamin C’s physiologic activities may be wider than previously believed. The notion that vitamin C could be effective in the treatment of cancer is a curious idea. Many believe that high doses of vitamin C will “boost” the immune system and help fight off an existing cancer. The problem with this concept is that most people who develop cancer have a normal immune system and the issue with immune recognition of cancer is generally one of specificity. We normally do not mount an effective response against our tumors, because we see them as “self.” The other idea is that vitamin C could actually directly kill a cancer cell. This notion is counterintuitive; however, it is based on in vitro observations, where ascorbic acid does kill cancer cells in vitro. The mechanism involved, however, is considered to be an in vitro artifact. Ascorbic acid is not directly transported by most cells, and in tissue culture there are free transition metals (iron and copper). Ascorbic acid reduces transition metals such as ferric ion to ferrous ion and generates hydrogen peroxide and free radicals via Fenton chemistry. These reactions are unlikely to occur in vivo, because transition metals are protein bound and, thus, sequestered. When cells are loaded in vitro with vitamin C by exposing them to the oxidized form of vitamin C, dehydroascorbic acid (DHA), the pro-oxidant effects of ascorbic acid are circumvented. Under these circumstances, vitamin C protects cells against radiation and oxidative stress in vitro. It would seem self-evident that if normal cells want and need vitamin C, cancer cells would also. Most of the popular concepts regarding the use of vitamin C in cancer fail to take into account the nutritional needs of the cancer cell itself. In 1993, we reported on a universal mechanism for vitamin C uptake by cells in the form of dehydroascorbic acid, which is transported without the expenditure of energy through the facilitative glucose transporters. These glucose transporters are up-regulated in cancer cells, and cancer cells take up more glucose and more vitamin C compared with their normal counterparts. Why do the cancer cells want vitamin C, and why have they developed a mechanism for preferentially acquiring it? Presumably, because the cancer cell is also threatened by oxidative attack, both from within and without. We have shown that cancer cells loaded with vitamin C become resistant to oxidative injury. What then is the theory or plausible concept by which vitamin C would be effective in cancer treatment? Vitamin C can have effects on signaling pathways; however, these have not been explored with regard to tumor cell viability. Could vitamin C protect normal cells from chemotherapy or radiation therapy? Yes, but would it not also protect cancer cells? The scientific conceptual basis for the use of vitamin C in the treatment of cancer is poorly supported, and the in vitro preclinical data are largely artifactual. Nonetheless, there have been various studies of the use of vitamin C in low and high dose, and in association with many other micronutrients in the treatment of cancer. A fair summary of the literature would be that the data are generally negative, but some studies are not well controlled or are poorly executed. Those who favor the notion that vitamin C is useful in treating cancer are unsatisfied by well-conducted negative studies, pointing again to the fact that it is difficult, Golde