Abstract

BackgroundAtorvastatin is a potent inhibitor of the mevalonate pathway and widely used as a hypolipidemic drug. Some epidemiological studies and animal experiments indicate that the long-term use of atorvastatin and structurally related drugs might be associated with a reduced risk of developing hepatocellular carcinoma (HCC), the most common hepatocellular malignancy in humans. However, the potential of atorvastatin to inhibit HCC formation is controversially discussed.MethodsHepatocellular tumors were chemically induced by treatment of C3H/He mice with 10 μg/g body weight N-nitrosodiethylamine and the ability of atorvastatin to interfere with tumor formation was investigated by treatment of mice with 0.1% atorvastatin in the diet for 6 months. Tumor size and tumor multiplicity were analyzed, as were tissue levels of cholesterol and atorvastatin.ResultsAtorvastatin treatment efficiently reduced serum cholesterol levels. However, the growth of tumors driven by activated MAPK (mitogen-activated protein kinase) signaling was not attenuated by the presence of the drug, as evidenced by a lack of reduction of tumor volume or tumor multiplicity by atorvastatin. Levels of the atorvastatin uptake transporters Oatp1a4 and Oatp1b2 were down-regulated at the mRNA and protein levels in chemically induced mouse liver tumors, but without striking effects on atorvastatin concentrations in the tumor tissue.ConclusionIn summary, the present data provide substantial evidence that atorvastatin does not beneficially influence tumor growth in mouse liver and thereby challenge the hypothesis that statin use might protect against hepatocellular cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-766) contains supplementary material, which is available to authorized users.

Highlights

  • Atorvastatin is a potent inhibitor of the mevalonate pathway and widely used as a hypolipidemic drug

  • Mouse hepatoma cell lines 53.2b, 55.1c, 70.4, and Hepa1c1c7 were screened for their expression of Hmgcs1 and 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr), encoding the first and rate-limiting steps in cholesterol biosynthesis

  • The ability of atorvastatin to interfere with hepatoma cell growth in vitro was tested at concentrations ranging from 1 μM to 20 μM, in order to meet the expected in vivo concentration of atorvastatin in mouse liver tumor cells

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Summary

Introduction

Atorvastatin is a potent inhibitor of the mevalonate pathway and widely used as a hypolipidemic drug. Some epidemiological studies and animal experiments indicate that the long-term use of atorvastatin and structurally related drugs might be associated with a reduced risk of developing hepatocellular carcinoma (HCC), the most common hepatocellular malignancy in humans. Statins are an important and widely used class of hypolipidemic drugs Their pharmacological efficacy is based on their ability to competitively inhibit 3-hydroxy-3-methyl-glutarylCoA reductase (HMGCR), an important and rate-limiting enzyme in the isoprenoid- and cholesterol-synthesizing mevalonate pathway. Apart from their lipid-lowering properties, several epidemiological studies evidence that the long-term use of statins in humans might be causally linked to a reduced risk of developing different types of cancer. No tumor-inhibitory effect of atorvastatin was detectable on the development of murine TSC2-associated liver hemangiosarcomas [29]

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