Biotechnology Program/RENORBIO, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil; Clinical Research Division, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil.
Pitágoras University, Linhares, ES, Brazil.
Pharmacol Rep. 2018 Jun;70(3):409-417. doi: 10.1016/j.pharep.2017.11.007. Epub 2017 Nov 21.
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. Primary cytoreductive surgery with adjuvant taxane-platinum chemotherapy is the standard treatment to fight ovarian cancer, however, their side effects are severe, and chemoresistance emerges at high rates. Therefore, EOC clinic urges for novel treatment strategies to reverse chemoresistance and to improve the survival rates. Metformin has been shown to act in synergy with certain anti-cancer agents, overcoming chemoresistance in various types of tumors. This paper aims to investigate the use of metformin as a new treatment option for cisplatin- and paclitaxel-resistant ovarian cancer.
The effects of metformin alone or in combination with conventional drugs on resistant EOC cell lines were investigated using the MTT assay for cell proliferation; Flow Cytometry analysis for cell cycle and the mRNA expression was analyzed using the real-time PCR technique.
We found that metformin exhibited antiproliferative effects in paclitaxel-resistant A2780-PR, and in cisplatin-resistant ACRP cell lines. The combined therapy containing conventional drugs and metformin improved the effect of the treatment in cell proliferation rate, especially in the resistant cells. We found that metformin, in clinical relevant doses, could significantly reduce the mRNA expression of inflammatory cytokines and NF-κB signaling pathway.
Taken together, our observations suggest that metformin inhibits the inflammatory pathway induced by paclitaxel and cisplatin treatment. Furthermore, metformin in combination with paclitaxel or cisplatin improved the sensitivity in drug-resistant ovarian cancer cells. Therefore, metformin may be beneficial treatment strategy, particularly in patients with tumors refractory to platinum and taxanes.
上皮性卵巢癌（EOC）仍然是最致命的妇科恶性肿瘤。辅以紫杉烷-铂类化疗的初次细胞减灭术是治疗卵巢癌的标准方法，然而，其副作用严重，且耐药性发生率高。因此，EOC 临床迫切需要新的治疗策略来逆转耐药性并提高生存率。二甲双胍已被证明可与某些抗癌药物协同作用，克服各种类型肿瘤的化疗耐药性。本文旨在研究二甲双胍作为治疗顺铂和紫杉醇耐药性卵巢癌的新方法。
使用 MTT 法检测细胞增殖，研究二甲双胍单独或联合常规药物对耐药性卵巢癌细胞系的作用；用流式细胞术分析细胞周期；采用实时 PCR 技术分析 mRNA 表达。
我们发现二甲双胍对紫杉醇耐药的 A2780-PR 和顺铂耐药的 ACRP 细胞系均表现出抗增殖作用。包含常规药物和二甲双胍的联合治疗可提高细胞增殖率的治疗效果，尤其是在耐药细胞中。我们发现，临床相关剂量的二甲双胍可显著降低与紫杉醇和顺铂治疗相关的炎症细胞因子和 NF-κB 信号通路的 mRNA 表达。
综上所述，我们的观察结果表明，二甲双胍可抑制紫杉醇和顺铂治疗诱导的炎症通路。此外，二甲双胍联合紫杉醇或顺铂可提高耐药性卵巢癌细胞对药物的敏感性。因此，二甲双胍可能是一种有益的治疗策略，尤其适用于对铂类和紫杉烷类药物耐药的肿瘤患者。
