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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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CDC2-CDC28 Kinases / drug effects
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CDC2-CDC28 Kinases / genetics
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CDC2-CDC28 Kinases / metabolism
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Cell Division / drug effects
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Cells, Cultured
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Cyclin D
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Cyclin E / drug effects
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Cyclin E / genetics
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2
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Cyclins / drug effects
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Cyclins / genetics
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Cyclins / metabolism
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Extracellular Matrix / drug effects
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Extracellular Matrix / metabolism
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G1 Phase / drug effects*
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Gene Expression / drug effects
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Gene Expression / physiology
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
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Matrix Metalloproteinase 2 / chemistry
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Matrix Metalloproteinase 9 / chemistry
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / prevention & control*
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Polyisoprenyl Phosphates / pharmacology
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Pravastatin / antagonists & inhibitors
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Pravastatin / pharmacology*
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Pravastatin / therapeutic use
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Randomized Controlled Trials as Topic
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Sesquiterpenes
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Umbilical Veins / cytology
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Umbilical Veins / drug effects
Substances
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Angiogenesis Inhibitors
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Cyclin D
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Cyclin E
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Cyclins
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Polyisoprenyl Phosphates
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Sesquiterpenes
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farnesyl pyrophosphate
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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Pravastatin
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geranylgeranyl pyrophosphate