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The statins, a family of cholesterol-lowering drugs, are known to block the formation of isoprenoids. They thus affect the small GTPase Rho, which requires attachment to cell membranes for proper signaling activity. Chimaerins are GTPase-activating proteins (GAPs) that accelerate GTP hydrolysis from Rac, another GTPase of the same family. We explored the cooperative antitumor effects of the overexpression of β2-chimaerin in combination with statins. F3II mouse mammary carcinoma cells transfected with the β2-chimaerin GAP domain exhibiting low intracellular levels of active Rac-GTP were exposed in vitro to a panel of statins. Transfectants were significantly more sensitive to the cytostatic effects of lovastatin, simvastatin, atorvastatin and rosuvastatin than untransfected F3II cells with high Rac-GTP levels. Transfected tumor cells also showed a higher sensitivity for detachment from the substrate and for apoptosis after statin exposure. We further checked the cytostatic effect of statins in combination with azathioprine, a compound that specifically blocks Rac1 activation. Combined treatment with simvastatin and azathioprine demonstrated an enhanced growth-inhibitory effect on control F3II cells. Our data suggest that the combination of statins with a reduction in active Rac levels can produce a cooperative antitumor effect on breast cancer cells.

Enhanced cytostatic activity of statins in mouse mammary carcinoma cells overexpressing β2-chimaerin