1. Curr Med Chem. 2009;16(15):1821-30.

In situ modulation of oxidative stress: a novel and efficient strategy to kill
cancer cells.

Verrax J, Pedrosa RC, Beck R, Dejeans N, Taper H, Calderon PB.

Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and
Cancer Biology Research Group (TOXCAN), PMNT, Brussels, Belgium.

Cancer cells show an up-regulation of glycolysis, they readily take up vitamin C,
and they appear more susceptible to an oxidative stress than the surrounding
normal cells. Here we compare, analyse and discuss these particular hallmarks by 
performing experiments in murine hepatomas (TLT cells) and freshly isolated mouse
hepatocytes. The results show that rates of lactate formation are higher in TLT
cells as compared to mouse hepatocytes, but their ATP content represents less
than 25% of that in normal cells. The uptake of vitamin C is more important in
hepatoma cells as compared to normal hepatocytes. This uptake mainly occurs
through GLUT1 transporters. Hepatoma cells have less than 10% of antioxidant
enzyme activities as compared to normal hepatocytes. This decrease includes not
only the major antioxidant enzymes, namely catalase, superoxide dismutase and
glutathione peroxidase, but also the GSH content. Moreover, catalase is almost
not expressed in hepatoma cells as shown by western blot analysis. We explored
therefore a selective exposure of cancer cells to an oxidative stress induced by 
pro-oxidant mixtures containing pharmacological doses of vitamin C and a redox
active compound such as menadione (vitamin K(3)). Indeed, the combination of
vitamin C (which accumulates in hepatoma cells) and a quinone undergoing a redox 
cycling (vitamin K(3)) leads to an oxidative stress that kills cancer cells in a 
selective manner. This differential sensitivity between cancer cells and normal
cells may have important clinical applications, as it has been observed with
other pro-oxidants like Arsenic trioxide, isothiocyanates, Adaphostin.

PMID: 19442148 [PubMed - indexed for MEDLINE]