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

Janine Kah; Andrea Wüstenberg; Amelie Keller; Hüseyin Sirma; Roberta Montalbano; Matthias Ocker; Tassilo Volz; Maura Dandri-Petersen; Gisa Tiegs; Gabriele Sass

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

Standard

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, Vol. 28, No. 3, 3, 2012, p. 1077-1083.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kah, J, Wüstenberg, A, Keller, A, Sirma, H, Montalbano, R, Ocker, M, Volz, T , Dandri-Petersen, M , Tiegs, G & Sass, G 2012, 'Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression.', ONCOL REP, vol. 28, no. 3, 3, pp. 1077-1083. <http://www.ncbi.nlm.nih.gov/pubmed/22710979?dopt=Citation>

APA

Kah, J., Wüstenberg, A., Keller, A., Sirma, H., Montalbano, R., Ocker, M., Volz, T., Dandri-Petersen, M., Tiegs, G., & Sass, G. (2012). Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. ONCOL REP, 28(3), 1077-1083. [3]. http://www.ncbi.nlm.nih.gov/pubmed/22710979?dopt=Citation

Vancouver

Kah J, Wüstenberg A, Keller A, Sirma H, Montalbano R, Ocker M et al. Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. ONCOL REP. 2012;28(3):1077-1083. 3.

Bibtex

@article{af44e01f95044c89a7ae2dea62723b92,

title = "Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression.",

abstract = "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.",

keywords = "Animals, Humans, Mice, Mice, Inbred C57BL, Gene Expression, Drug Screening Assays, Antitumor, Cell Survival/drug effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology, Antineoplastic Agents/*pharmacology, Tumor Suppressor Protein p53/genetics/*metabolism, Pyrimidines/pharmacology, Apoptosis/*drug effects, Indoles/pharmacology, Carcinoma, Hepatocellular/*drug therapy, Cell Line, Tumor/drug effects, Cholesterol/biosynthesis, Fatty Acids, Monounsaturated/pharmacology, Fluorobenzenes/pharmacology, Heptanoic Acids/pharmacology, Lipid Metabolism/drug effects, Liver Neoplasms/*drug therapy, Lovastatin/pharmacology, Pyrroles/pharmacology, Simvastatin/pharmacology, Sulfonamides/pharmacology, Animals, Humans, Mice, Mice, Inbred C57BL, Gene Expression, Drug Screening Assays, Antitumor, Cell Survival/drug effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology, Antineoplastic Agents/*pharmacology, Tumor Suppressor Protein p53/genetics/*metabolism, Pyrimidines/pharmacology, Apoptosis/*drug effects, Indoles/pharmacology, Carcinoma, Hepatocellular/*drug therapy, Cell Line, Tumor/drug effects, Cholesterol/biosynthesis, Fatty Acids, Monounsaturated/pharmacology, Fluorobenzenes/pharmacology, Heptanoic Acids/pharmacology, Lipid Metabolism/drug effects, Liver Neoplasms/*drug therapy, Lovastatin/pharmacology, Pyrroles/pharmacology, Simvastatin/pharmacology, Sulfonamides/pharmacology",

author = "Janine Kah and Andrea W{\"u}stenberg and Amelie Keller and H{\"u}seyin Sirma and Roberta Montalbano and Matthias Ocker and Tassilo Volz and Maura Dandri-Petersen and Gisa Tiegs and Gabriele Sass",

year = "2012",

language = "English",

volume = "28",

pages = "1077--1083",

journal = "ONCOL REP",

issn = "1021-335X",

publisher = "Spandidos Publications",

number = "3",

}

RIS

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