Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression

HMG-CoA-reductase inhibitors (statins) are widely used drugs to interferewith cholesterol biosynthesis. Besides this usage, evidence is increasing thatstatins might also be useful in therapy of viral infections or cancer. We investigatedthe effects of fluva-, simva-, atorva-, rosuva- and lovastatin on the viabilityof primary mouse and human hepatocytes as well as mouse (Hepa1-6) and human (Huh7,HepG2) hepatoma cell lines. Our results show selective cytotoxic effects of fluva-,simva- and lovastatin on hepatoma cells in comparison to primary hepatocytes.Using human hepatoma cells we found significant reduction of cell viability andinduction of apoptosis in HepG2 cells, while statins did not affect Huh7 cellsat concentrations not toxic for primary hepatocytes. Stable knockdown of endogenousp53, which is overexpressed in Huh7 cells, was able to restore susceptibilityof Huh7 cells towards statin-induced toxicity. The anti-tumor effect of statinsdid not depend on a lack of cholesterol production, but was restored by supplementationof mevalonate or geranyl-geranyl pyrophosphate, prerequisites for prenylationof small G proteins. In conclusion, statins display a selective apoptotic effecton human hepatoma cells, with fluva-, simva- and lovastatin being both, most selectivefor tumor cells and most effective in inducing tumor cell apoptosis. Additionally,our results implicate that anti-tumor activity of statins requires cell proliferationand is reduced by p53 overexpression.