3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on cell cycle arrest

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Objective: 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. Methods: Using the human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of pravastatin, kindly gifted by Sankyo Co., Ltd., on the various steps of angiogenesis, including endothelial cells’ proliferation and adhesion to extracellular matrix proteins. Results: 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, E and cyclin-dependent kinase (CDK) 2 levels. Also pravastatin inhibited tube formation on matrigel and adhesion to extracellular matrix, but did not affect matrix metalloproteinase production. Conclusions: Angiogenesis is essential for tumor development and progression, and consequently, inhibition of angiogenesis may be an attractive strategy for the treatment of cancer. The present results demonstrate the anti-angiogenic activity of pravastatin and its potential use as an anticancer drug is suggested.