The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism.
The endocannabinoid system has been shown to modulate key cell-signaling pathways involved in cancer cell growth. In this study, we show that cannabinoid receptor type 1 (CB1) 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 antiproliferative 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 kinase inhibitor p27KIP1. We have also shown that SR141716 exerted a significant antiproliferative 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 antiproliferative effect in tumor cells, we did not observe evidence of any genotoxic effect on normal cells. Our data also indicate that the SR141716 antiproliferative effect requires lipid raft/caveolae integrity to occur. Indeed, we found that CB1 receptor (CB1R) is completely displaced from lipid rafts in SR141716-treated MDA-MB-231 cells, and cholesterol depletion by methyl-beta-cyclodextrin strongly prevented SR141716-mediated antiproliferative effect. Taken together, our results suggest that SR141716 inhibits human breast cancer cell growth via a CB1R lipid raft/caveolae-mediated mechanism.
Sarnataro
Daniela
D
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte don Melillo, 84084 Fisciano (Salerno), Italy.
Pisanti
Simona
S
Santoro
Antonietta
A
Gazzerro
Patrizia
P
Malfitano
Anna Maria
AM
Laezza
Chiara
C
Bifulco
Maurizio
M
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016466:CHO Cells; D021941:Caveolae / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077285:Rimonabant; D014183:Transplantation, Heterologous / Q000473:pathology*; D047368:Tumor Burden
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant