title: Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice.
abstract: Hepatocellular carcinoma (HCC) represents approximately 85% of all primary liver cancer cases. Non-alcoholic fatty liver disease (NAFLD) is one of the risk factors for HCC. NAFLD occurs in patients with components of metabolic syndrome, such as type 2 diabetes mellitus, obesity, hypertension and hyperlipidemia. Therefore, hyperlipidemia also represents a patient population at risk for HCC that can readily be identified. Rosuvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has exhibited a more potent affinity for the active site of HMG-CoA reductase than other statins. In addition, the hepatic uptake of rosuvastatin in rats has been found to be more selective and efficient than that with other drugs. Furthermore, the cytoprotective effects of rosuvastatin against ischemic injury have been clearly reported. Thus, in this study, we aimed to determine the role of rosuvastatin as a preventive drug in HCC associated with NAFLD. STAM mice, which developed HCC from NAFLD by being fed a high-fat diet (HFD), were divided into a group in which a HFD was given to the mice for 15 weeks (n=8) and another in which a HFD supplemented with 0.00125% rosuvastatin was given to the mice for 15 weeks (n=8). Rosuvastatin inhibited the development of hepatic tumors in the mice with NAFLD induced by a specific diet both macroscopically and histologically. Rosuvastatin significantly decreased the expression levels of pro-inflammatry cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β1. Tumor aggressiveness is mediated by angiogenic factors. Therefore, we examined the hepatic mRNA expression of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF). The hepatic expression of these factors significantly decreased in the rousvastin-fed mice. Our results thus suggest rosuvastatin that prevents carcinogenesis and improves the hepatic background. Our data suggest that rosuvastatin has potential for use as a preventive drug for the development of HCC associated with NAFLD in mice.
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yokohama
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukunishi
authors.affiliation: Department of Pharmacology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Ohama
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tsuchimoto
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuda
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D004032:Diet; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007249:Inflammation / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D000068718:Rosuvastatin Calcium