Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo, 84084 Fisciano, Salerno, Italy.
Pharmacol Res. 2012 Mar;65(3):365-71. doi: 10.1016/j.phrs.2011.11.008. Epub 2011 Nov 22.
Emerging findings suggested the efficacy of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in several pathological conditions included tumours. In this study we investigated in vitro the effects of SR141716 on viability and the molecular pathways of methylcholanthrene-induced fibrosarcoma (Meth-A) cells and in vivo its anti-tumour properties in Meth-A-bearing mice. We evaluated in vitro the effect of SR141716 on Meth-A cell viability by trypan blue staining assay. Cell cycle progression and apoptosis were assessed by flow cytometry. Protein expression was investigated by Western blot. The anti-tumour efficacy of SR141716 was evaluated in vivo monitoring weight increase and survival of Meth-A injected mice. SR141716 affects Meth-A cell viability inducing apoptosis and controls cell cycle progression by modulation of the levels of the cell cycle inhibitor p21waf, cyclins E, D1 and NF-kB molecules. Importantly, SR141716 affects AKT/pFoxO1 pathway which promotes cell survival and regulates the cell cycle. The molecular effects observed are accompanied by reduced COX2 expression and induction of the CB1 receptor expression. Finally, SR141716 was able to reduce the tumour size and prolong animal survival, when administered in vivo during tumour growth. Our findings shed light on a novel molecular pathway associated with control of tumour growth by SR141716 and confirm the anti-cancer and anti-inflammatory properties of this drug suggesting its potential applications in the treatment of cancer.
新兴的研究结果表明，大麻素 CB1 受体拮抗剂利莫那班（SR141716）在多种病理情况下（包括肿瘤）具有疗效。在这项研究中，我们研究了 SR141716 对甲基胆蒽诱导的纤维肉瘤（Meth-A）细胞活力和分子途径的体外影响，以及在 Meth-A 荷瘤小鼠体内的抗肿瘤特性。我们通过台盼蓝染色法评估了 SR141716 对 Meth-A 细胞活力的体外影响。通过流式细胞术评估细胞周期进展和细胞凋亡。通过 Western blot 检测蛋白表达。通过监测 Meth-A 注射小鼠的体重增加和存活率来评估 SR141716 的抗肿瘤疗效。SR141716 通过诱导细胞凋亡和调节细胞周期抑制剂 p21waf、细胞周期蛋白 E、D1 和 NF-kB 分子的水平来影响 Meth-A 细胞活力并控制细胞周期进程。重要的是，SR141716 影响 AKT/pFoxO1 通路，促进细胞存活并调节细胞周期。观察到的分子效应伴随着 COX2 表达的降低和 CB1 受体表达的诱导。最后，当在肿瘤生长期间体内给予 SR141716 时，它能够减小肿瘤大小并延长动物的存活时间。我们的研究结果揭示了与 SR141716 控制肿瘤生长相关的新分子途径，并证实了该药物的抗癌和抗炎特性，表明其在癌症治疗中的潜在应用。
