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 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.
Institute of Experimental Immunology and Hepatology, Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Janine
J
Kah
Andrea
A
Wüstenberg
Amelie Dorothea
AD
Keller
Hüseyin
H
Sirma
Roberta
R
Montalbano
Matthias
M
Ocker
Tassilo
T
Volz
Maura
M
Dandri
Gisa
G
Tiegs
Gabriele
G
Sass
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D000077340:Fluvastatin; D015870:Gene Expression; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin