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Received for publication April 12, 2006.
Revised June 29, 2006.
Accepted for publication July 5, 2006.
The endocannabinoid system has been shown to modulate key cell-signalling pathways involved in cancer cell growth. In this study we show that CB1 cannabinoid receptor antagonist Rimonabant (SR141716) inhibited human breast cancer cell proliferation, being more effective in highly invasive metastatic MDA-MB-231 cells, than in less invasive T47D and MCF-7 cells. The SR141716 anti-proliferative effect was not accompanied by apoptosis or necrosis and was characterized by a G1/S phase cell cycle arrest, decreased expression of cyclin D and E and increased levels of cyclin-dependent kinases inhibitor p27KIP1. We have also shown that SR141716 exerted a significant anti-proliferative action, in vivo, by reducing the volume of xenograft tumors induced by MDA-MB-231 injection in mice. On the other hand, at the concentration range in which we observed the anti-proliferative effect in tumor cells, we did not evidence any genotoxic effect on normal cells. Our data also indicate that the SR141716 anti-proliferative effect requires lipid rafts/caveolae integrity to occur. Indeed, we found that CB1 receptor is completely displaced from lipid rafts in SR141716 treated MDA-MB-231 cells and cholesterol depletion by methyl-beta-cyclodextrin strongly prevented SR141716-mediated anti-proliferative effect. Taken together, our results suggest that SR141716 inhibits human breast cancer cell growth via a CB1 receptor lipid rafts/caveolae-mediated mechanism.
Key words:
Cannabinoid, Lipid rafts/microdomains, MAP Kinase, Membrane targets
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