title: Chemoprevention of mouse lung and colon tumors by suberoylanilide hydroxamic acid and atorvastatin.
abstract: Atorvastatin and suberoylanilide hydroxamic acid (SAHA) were evaluated for chemoprevention of mouse lung tumors. In Experiment 1, lung tumors were induced by vinyl carbamate in strain A/J mice followed by 500 mg/kg SAHA, 60 or 180 mg/kg atorvastatin, and combinations containing SAHA and atorvastatin administered in their diet. SAHA and both combinations, but not atorvastatin, decreased the multiplicity of lung tumors, including large adenomas and adenocarcinomas with the combinations demonstrating the greatest efficacy. In Experiment 2, lung tumors were induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol in strain A/J mice followed by 180 mg/kg atorvastatin, 500 mg/kg SAHA, or both drugs administered in the diet. SAHA and the combination of both drugs, but not atorvastatin alone, decreased the multiplicity of lung tumors and large tumors, with the combination demonstrating greater efficacy. In Experiment 3, lung tumors were induced by 1,2-dimethylhydrazine in Swiss-Webster mice followed by 160 mg/kg atorvastatin, 400 mg/kg SAHA, or a combination of both drugs administered in the diet. SAHA and the combination, but not atorvastatin, decreased the multiplicity of lung tumors with the combination demonstrating greater efficacy. The multiplicity of colon tumors was decreased by SAHA, atorvastatin, and the combination, without any significant difference in their efficacy. mRNA expression analysis of lung tumor bearing mice suggested that the enhanced chemopreventive activity of the combination is related to atorvastatin modulation of DNA repair, SAHA modulation of angiogenesis, and both drugs modulating invasion and metastasis pathways. Atorvastatin demonstrated chemoprevention activity as indicated by the enhancement of the efficacy of SAHA to prevent mouse lung tumors.
authors.affiliation: College of Medicine, Division of Medical Oncology, and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. michael.pereira@osumc.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pereira
authors.forename: Blake M
authors.initials: BM
authors.lastname: Warner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Knobloch
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Weghorst
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Casto
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D004127:Dimethylhydrazines / Q000633:toxicity; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D014520:Urethane / Q000031:analogs & derivatives / Q000633:toxicity; D000077337:Vorinostat
chemical_list: D004127:Dimethylhydrazines; D006538:Heptanoic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009602:Nitrosamines; D011758:Pyrroles; D012333:RNA, Messenger; D014520:Urethane; D000077337:Vorinostat; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C017963:vinyl carbamate; D000069059:Atorvastatin