Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Prostate Cancer Prostatic Dis. 2012 Dec;15(4):346-52. doi: 10.1038/pcan.2012.16. Epub 2012 May 22.
Prostate cancer incidence and mortality vary dramatically by geographical location. Both are higher in developed countries. Some attribute this to westernized lifestyles of high-energy diets and limited physical activity with consequent obesity. Obesity and obesity-related diseases like diabetes cause hyperinsulinaemia, which upregulates pro-survival cell signalling. Previous work revealed diet-induced hyperinsulinaemia enhances prostate cancer xenograft growth in vivo. Metformin, an antidiabetic medication, reduces hyperinsulinaemia and also exhibits antineoplastic properties. Herein, we assess the potential additive benefit of combining bicalutamide antiandrogen therapy with metformin, in vitro and in vivo.
Using clonogenic assays, we assessed the effect of bicalutamide and/or metformin on clonogenicity in prostate cancer cell lines. Western blot and cell cycle analyses were used to elucidate mechanisms of interaction between the drugs in androgen receptor (AR)-positive (LNCaP) and AR-negative (PC3) cell lines. The combination treatment regimen was assessed in vivo using an LNCaP murine xenograft model.
Micromolar bicalutamide or millimolar metformin caused a significant dose-dependent reduction in clonogenicity (P<0.001). Combination treatment further significantly reduced clonogenicity (P<0.005) with greater effects in AR-positive cells. Western blot and cell cycle analyses suggested differing mechanisms of interaction in AR-positive and -negative cell lines. Following combination treatment, LNCaP cells exhibited an altered cell proliferation (decreased phospho mammalian target of rapamycin expression) and perturbed cell cycle kinetics (G1/S cell cycle arrest). PC3 cells showed evidence of enhanced apoptosis (increased Bcl-2-associated X protein and decreased total caspase 3 expression). Markedly diminished tumour growth occurred following combination treatment in vivo (P<0.001).
Combining bicalutamide and metformin significantly reduces prostate cancer cell growth further than either monotherapy. In AR-positive cells, this effect appeared to be mediated by reducing proliferation rates, whereas in AR-negative cells the combination treatment appeared to promote apoptosis. This combination drug regimen may improve prostate-cancer-specific survival by the direct antineoplastic properties outlined.
前列腺癌的发病率和死亡率在地理位置上差异很大。在发达国家，这两个数据都更高。一些人将其归因于高热量饮食和缺乏体力活动导致肥胖的西方化生活方式。肥胖和肥胖相关疾病（如糖尿病）会导致高胰岛素血症，从而上调促生存细胞信号。先前的工作表明，饮食诱导的高胰岛素血症会增强体内前列腺癌异种移植物的生长。二甲双胍是一种抗糖尿病药物，可降低高胰岛素血症，并且具有抗肿瘤特性。在此，我们评估了将比卡鲁胺抗雄激素治疗与二甲双胍联合使用的潜在附加益处，包括体外和体内。
使用集落形成实验，我们评估了比卡鲁胺和/或二甲双胍对前列腺癌细胞系集落形成的影响。使用 Western blot 和细胞周期分析来阐明在雄激素受体（AR）阳性（LNCaP）和 AR 阴性（PC3）细胞系中药物相互作用的机制。使用 LNCaP 小鼠异种移植模型评估联合治疗方案。
微摩尔浓度的比卡鲁胺或毫摩尔浓度的二甲双胍会导致集落形成能力显著降低（P<0.001）。联合治疗进一步显著降低了集落形成能力（P<0.005），对 AR 阳性细胞的作用更大。Western blot 和细胞周期分析表明，在 AR 阳性和阴性细胞系中存在不同的相互作用机制。联合治疗后，LNCaP 细胞表现出改变的细胞增殖（磷酸化哺乳动物雷帕霉素靶蛋白表达减少）和扰乱的细胞周期动力学（G1/S 细胞周期停滞）。PC3 细胞显示出增强的细胞凋亡（Bcl-2 相关 X 蛋白增加，总半胱氨酸天冬氨酸蛋白酶 3 表达减少）的证据。体内联合治疗后，肿瘤生长明显减少（P<0.001）。
将比卡鲁胺和二甲双胍联合使用可进一步降低前列腺癌细胞的生长，比单独使用任何一种药物效果都要好。在 AR 阳性细胞中，这种作用似乎是通过降低增殖率来介导的，而在 AR 阴性细胞中，联合治疗似乎促进了细胞凋亡。这种联合药物治疗方案可能通过直接的抗肿瘤特性来提高前列腺癌的特异性生存。
