HMG-CoA-reductase inhibitors (
statins) are widely used drugs to interfere with
cholesterol biosynthesis. Besides this usage, evidence is increasing that
statins might also be useful in
therapy of
viral infections or
cancer. We investigated the effects of fluva-, simva-, atorva-, rosuva- and
lovastatin on the viability of 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 and induction of apoptosis in HepG2 cells, while
statins did not affect Huh7 cells at concentrations not toxic for primary hepatocytes. Stable knockdown of endogenous p53, which is overexpressed in Huh7 cells, was able to restore susceptibility of Huh7 cells towards
statin-induced toxicity. The anti-
tumor effect of
statins did not depend on a lack of
cholesterol production, but was restored by supplementation of
mevalonate or geranyl-
geranyl pyrophosphate, prerequisites for prenylation of
small G proteins. In conclusion,
statins display a selective apoptotic effect on human
hepatoma cells, with fluva-, simva- and
lovastatin being both, most selective for
tumor cells and most effective in inducing
tumor cell apoptosis. Additionally, our results implicate that anti-
tumor activity of
statins requires cell proliferation and is reduced by p53 overexpression.