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Enhanced Antitumor Activity of Vitamin C via P53 in Cancer Cells

Vitamin C is water-soluble, and probably the most famous of all the vitamins. Even before its discovery in 1932, physicians recognised that there must be a compound in citrus fruits preventing scurvy, a disease that killed as many as 2 million sailors between 1500 and 1800. Later researchers discovered that man, other primates and the guinea pig depend on external sources to cover their Vitamin C requirements. Most other animals are able to synthesise Vitamin C from glucose and galactose in their body. The most prominent role of Vitamin C is its immune stimulating effect, which is important for the defence against infections such as common colds. It also acts as an inhibitor of histamine, a compound that is released during allergic reactions. As a powerful antioxidant it can neutralise harmful free radicals and aids in neutralising pollutants and toxins.

Kim J, Lee SD, Chang B, Jin DH, Jung SI, Park MY, Han Y, Yang Y, Il Kim K, Lim JS, Kang YS, Lee MS. Enhanced antitumor activity of Vitamin C via p53 in cancer cells. 1. Free Radic Biol Med. 2012 Aug 4. [Epub ahead of print]

Ascorbate is an important natural antioxidant that can selectively kill cancer cells at pharmacological concentrations. Despite its benefit, it is quite difficult to predict the antitumor effects of ascorbate, because the relative cytotoxicity of ascorbate differs between cancer cell lines. Therefore, it is essential to examine the basis for this fundamental disagreement. Because p53 is activated by DNA-damaging stress and then regulates various cellular conditions, we hypothesized that p53 can sensitize cancer cells to ascorbate. Using isogenic cancer cells, we observed that the presence of p53 can affect ascorbate cytotoxicity, and also reactivation of p53 can make cancer cells sensitive to ascorbate. p53-dependent enhancement of ascorbate cytotoxicity is caused by increased reactive oxygen species generation via a differentially regulated p53 transcriptional network. We also found that transcriptionally activated p53 was derived from MDM2 ubiquitination by ascorbate and subsequently its signaling network renders cancer cells more susceptible to oxidative stress. Similar to the p53 effect on in vitro ascorbate cytotoxicity, inhibition of tumor growth is also stronger in p53-expressing tumors than in p53-deficient ones in vivo. This is the first observation that ascorbate cytotoxicity is positively related to p53 expression, activating its transcriptional network to worsen intracellular oxidative stress and consequently enhancing its cytotoxicity. Based on our study, reactivation of p53 may help to achieve more consistent cytotoxic effects of ascorbate in cancer therapies.