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大麻素CB1受体拮抗剂利莫那班(SR141716)通过脂筏介导的机制抑制人乳腺癌细胞增殖。

The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism.

作者信息

Sarnataro Daniela, Pisanti Simona, Santoro Antonietta, Gazzerro Patrizia, Malfitano Anna Maria, Laezza Chiara, Bifulco Maurizio

机构信息

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte don Melillo, 84084 Fisciano (Salerno), Italy.

出版信息

Mol Pharmacol. 2006 Oct;70(4):1298-306. doi: 10.1124/mol.106.025601. Epub 2006 Jul 5.

Abstract

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.

摘要

内源性大麻素系统已被证明可调节参与癌细胞生长的关键细胞信号通路。在本研究中,我们发现大麻素1型(CB1)拮抗剂利莫那班(SR141716)可抑制人乳腺癌细胞增殖,对高侵袭性转移性MDA-MB-231细胞的抑制作用比对侵袭性较低的T47D和MCF-7细胞更有效。SR141716的抗增殖作用并非伴随着细胞凋亡或坏死,其特征是G1/S期细胞周期停滞、细胞周期蛋白D和E的表达降低以及细胞周期蛋白依赖性激酶抑制剂p27KIP1水平升高。我们还表明,SR141716在体内通过减少小鼠注射MDA-MB-231诱导的异种移植肿瘤体积发挥显著的抗增殖作用。另一方面,在我们观察到对肿瘤细胞具有抗增殖作用的浓度范围内,未观察到对正常细胞有任何遗传毒性作用的证据。我们的数据还表明,SR141716的抗增殖作用需要脂筏/小窝的完整性才能发生。事实上,我们发现CB1受体(CB1R)在经SR141716处理的MDA-MB-231细胞中完全从脂筏中移位,而甲基-β-环糊精消耗胆固醇可强烈阻止SR141716介导的抗增殖作用。综上所述,我们的结果表明,SR141716通过CB1R脂筏/小窝介导的机制抑制人乳腺癌细胞生长。

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