title: Chemically induced mouse liver tumors are resistant to treatment with atorvastatin.
abstract: BACKGROUND
  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. However, the potential of atorvastatin to inhibit HCC formation is controversially discussed.
  
  
  METHODS
  Hepatocellular 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.
  
  
  RESULTS
  Atorvastatin 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tuebingen, Wilhelmstr, 56, Tuebingen 72074, Germany. albert.braeuning@uni-tuebingen.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Philip
authors.initials: P
authors.lastname: Bucher
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.forename: Albrecht
authors.initials: A
authors.lastname: Buchmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000069059:Atorvastatin; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D009154:Mutation; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; C464433:Oatp2 protein, mouse; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D011758:Pyrroles; C498887:Slco1b2 protein, mouse; D000069059:Atorvastatin; D048493:Proto-Oncogene Proteins B-raf