Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Oncol Rep. 2014 Jun;31(6):2611-8. doi: 10.3892/or.2014.3151. Epub 2014 Apr 23.
Metformin is an oral anti-hyperglycemic agent of the biguanide family, which is used first-line for type II diabetes with few side-effects. A recent epidemiological study that included 1,828 potential intrahepatic cholangiocarcinoma (ICC) patients showed that metformin use was significantly associated with a 60% reduction in ICC risk in diabetic patients, demonstrating the potential value of metformin in ICC management. In the present study, we firstly showed that metformin exhibited a dose- and time-dependent anti-proliferation effect on ICC cell lines, by mechanisms including apoptosis induction and cell cycle arrest. Metformin targeted the AMPK/mTORC1 pathway in ICC cells. Furthermore, metformin sensitized ICC cells to certain chemotherapeutic agents, such as sorafenib, 5-fluorouracil and As2O3 by targeting the AMPK/mTOR/HIF-1α/MRP1 pathway and ERK. As it is an inexpensive and widely used antidiabetic drug without severe adverse effects, metformin may be a prospective chemotherapeutic agent or a chemosensitizer in future ICC treatment.
二甲双胍是一种双胍类的口服抗高血糖药物，是治疗 II 型糖尿病的一线药物，副作用较少。最近一项包含 1828 名潜在肝内胆管癌（ICC）患者的流行病学研究表明，二甲双胍的使用与糖尿病患者 ICC 风险降低 60%显著相关，这表明二甲双胍在 ICC 管理方面具有潜在价值。在本研究中，我们首次表明，二甲双胍通过诱导细胞凋亡和细胞周期阻滞等机制，对 ICC 细胞系表现出剂量和时间依赖性的抗增殖作用。二甲双胍靶向 ICC 细胞中的 AMPK/mTORC1 通路。此外，二甲双胍通过靶向 AMPK/mTOR/HIF-1α/MRP1 通路和 ERK，使 ICC 细胞对某些化疗药物（如索拉非尼、5-氟尿嘧啶和亚砷酸）更加敏感。由于二甲双胍是一种廉价且广泛使用的抗糖尿病药物，没有严重的不良反应，因此它可能成为未来 ICC 治疗中的一种有前途的化疗药物或化疗增敏剂。
