Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Hengzhigang Road 78#, Guangzhou, 510095, Guangdong, People's Republic of China.
Mol Cell Biochem. 2014 Jan;386(1-2):63-71. doi: 10.1007/s11010-013-1845-x. Epub 2013 Oct 6.
Breast cancer is the most frequently diagnosed tumor type and the primary leading cause of cancer deaths in women worldwide and multidrug resistance is the major obstacle for breast cancer treatment improvement. Emerging evidence suggests that metformin, the most widely used antidiabetic drug, resensitizes and cooperates with some anticancer drugs to exert anticancer effect. However, there are no data regarding the reversal effect of metformin on chemoresistance in breast cancer. In the present study, we investigated the resistance reversal effect of metformin on acquired multidrug-resistant breast cancer cells MCF-7/5-Fu derived from MCF-7 breast cancer cells and innate multidrug-resistant MDA-MB-231 breast cancer cells, and we found that metformin resensitized MCF7/5-FU and MDA-MB-231 to 5-fluorouracil (5-FU), adriamycin, and paclitaxel. We also observed that metformin reversed epithelial-mesenchymal transition (EMT) phenotype and decreased the invasive capacity of MCF7/5-FU and MDA-MB-231 cells. However, there were no significant changes upon metformin-treated MCF7 cells. Moreover, we found metformin treatment activated AMPK signal pathway in MCF7/5-FU and MDA-MB-231 cells and compound C, the AMPK inhibitor, could partly abolish the resensitization and EMT reversal effect of metformin. To the best of our knowledge, we are the first to report that metformin can resensitize multidrug-resistant breast cancer cells due to activating AMPK signal pathway. Our study will help elucidate the mechanism of chemoresistance and establish new strategies of chemotherapy for human breast cancer.
乳腺癌是全球女性中最常见的肿瘤类型和癌症死亡的主要原因，多药耐药是乳腺癌治疗改善的主要障碍。新出现的证据表明，二甲双胍是最广泛使用的抗糖尿病药物，它可以使耐药细胞重新敏感，并与一些抗癌药物协同作用发挥抗癌作用。然而，关于二甲双胍对乳腺癌化疗耐药性的逆转作用尚无数据。在本研究中，我们研究了二甲双胍对来源于 MCF-7 乳腺癌细胞的获得性多药耐药 MCF-7/5-Fu 细胞和固有多药耐药 MDA-MB-231 乳腺癌细胞的耐药逆转作用，我们发现二甲双胍使 MCF7/5-FU 和 MDA-MB-231 对 5-氟尿嘧啶（5-FU）、阿霉素和紫杉醇重新敏感。我们还观察到二甲双胍逆转了 MCF7/5-FU 和 MDA-MB-231 细胞的上皮-间充质转化（EMT）表型并降低了其侵袭能力。然而，在二甲双胍处理的 MCF7 细胞中没有观察到显著变化。此外，我们发现二甲双胍处理激活了 MCF7/5-FU 和 MDA-MB-231 细胞中的 AMPK 信号通路，而 AMPK 抑制剂化合物 C 可以部分消除二甲双胍的再敏化和 EMT 逆转作用。据我们所知，我们是第一个报道二甲双胍可以通过激活 AMPK 信号通路使多药耐药乳腺癌细胞重新敏感的。我们的研究将有助于阐明化疗耐药的机制，并为人类乳腺癌建立新的化疗策略。
