Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression.
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Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. / Kah, Janine; Wüstenberg, Andrea; Keller, Amelie; Sirma, Hüseyin; Montalbano, Roberta; Ocker, Matthias; Volz, Tassilo; Dandri-Petersen, Maura; Tiegs, Gisa; Sass, Gabriele.
in: ONCOL REP, Jahrgang 28, Nr. 3, 3, 2012, S. 1077-1083.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression.
AU - Kah, Janine
AU - Wüstenberg, Andrea
AU - Keller, Amelie
AU - Sirma, Hüseyin
AU - Montalbano, Roberta
AU - Ocker, Matthias
AU - Volz, Tassilo
AU - Dandri-Petersen, Maura
AU - Tiegs, Gisa
AU - Sass, Gabriele
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression
KW - Drug Screening Assays, Antitumor
KW - Cell Survival/drug effects
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - Pyrimidines/pharmacology
KW - Apoptosis/drug effects
KW - Indoles/pharmacology
KW - Carcinoma, Hepatocellular/drug therapy
KW - Cell Line, Tumor/drug effects
KW - Cholesterol/biosynthesis
KW - Fatty Acids, Monounsaturated/pharmacology
KW - Fluorobenzenes/pharmacology
KW - Heptanoic Acids/pharmacology
KW - Lipid Metabolism/drug effects
KW - Liver Neoplasms/drug therapy
KW - Lovastatin/pharmacology
KW - Pyrroles/pharmacology
KW - Simvastatin/pharmacology
KW - Sulfonamides/pharmacology
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression
KW - Drug Screening Assays, Antitumor
KW - Cell Survival/drug effects
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
KW - Antineoplastic Agents/pharmacology
KW - Tumor Suppressor Protein p53/genetics/metabolism
KW - Pyrimidines/pharmacology
KW - Apoptosis/drug effects
KW - Indoles/pharmacology
KW - Carcinoma, Hepatocellular/drug therapy
KW - Cell Line, Tumor/drug effects
KW - Cholesterol/biosynthesis
KW - Fatty Acids, Monounsaturated/pharmacology
KW - Fluorobenzenes/pharmacology
KW - Heptanoic Acids/pharmacology
KW - Lipid Metabolism/drug effects
KW - Liver Neoplasms/drug therapy
KW - Lovastatin/pharmacology
KW - Pyrroles/pharmacology
KW - Simvastatin/pharmacology
KW - Sulfonamides/pharmacology
M3 - SCORING: Journal article
VL - 28
SP - 1077
EP - 1083
JO - ONCOL REP
JF - ONCOL REP
SN - 1021-335X
IS - 3
M1 - 3
ER -