title: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest.
abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been developed as lipid-lowering drugs, and are well recognized to reduce morbidity and mortality from coronary artery disease. Several recent experimental studies have focused on the inhibitory effects of HMG-CoA reductase inhibitor on tumor cell growth in vitro and in vivo, dependent on a direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of pravastatin and its mechanism of action. Using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of pravastatin on the various steps of angiogenesis, including endothelial cell proliferation and adhesion to extracellular matrix proteins. Pravastatin induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis. G1 arrest was due to the decrease of cyclin D, cyclin E and cyclin-dependent kinase 2 levels. In addition, pravastatin inhibited tube formation on Matrigel and adhesion to extracellular matrix, but did not affect matrix metalloproteinase production. The present results demonstrate the anti-angiogenic activity of pravastatin and its potential use as an anticancer drug is suggested.
authors.affiliation: Departments of Surgical Oncology, Transfusion Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. asakage-dis@h.u-tokyo.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asakage
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Tsuno
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kawai
authors.forename: Yurai
authors.initials: Y
authors.lastname: Okaji
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yazawa
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kaisaki
authors.forename: Koki
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagawa
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D042846:CDC2-CDC28 Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D019927:Cyclin E / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D016213:Cyclins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017035:Pravastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012717:Sesquiterpenes; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate