title: Metformin potentiates the anticancer activities of gemcitabine and cisplatin against cholangiocarcinoma cells in vitro and in vivo.
abstract: Metformin, an oral biguanide drug used to treat type 2 diabetes, has displayed anticancer activities in several types of cancer cells. The combination of gemcitabine and cisplatin is the standard chemotherapy regimen for cholangiocarcinoma, but its benefit is limited. The present study aimed to investigate whether metformin could enhance the activities of gemcitabine and cisplatin against cholangiocarcinoma, and the underlying mechanisms. Metformin inhibited the proliferation of human cholangiocarcinoma RBE and HCCC-9810 cells and induced cell cycle arrest at the G0/G1 phase by increasing the activation of AMP-activated protein kinase (AMPK) pathways. Metformin upregulated the expression of p21Waf1 and p27kip1, and downregulated the expression of cyclin D1, a key protein required for cell cycle progression. The combination of gemcitabine and cisplatin inhibited the proliferation and induced the apoptosis of human cholangiocarcinoma cells by inducing the phosphorylation of AMPK, downregulating cyclin D1, and activating caspase-3. Administration of metformin enhanced the efficacy of gemcitabine and cisplatin to suppress the growth of cholangiocarcinoma tumors established in experimental models by inhibiting cell proliferation and inducing cell apoptosis through their effects on AMPK, cyclin D1 and caspase-3. Given that metformin has been used to treat type 2 diabetes patients for over half a century due to its superior safety profile, the results presented here indicate that metformin may be a potent agent for enhancing the efficacy of gemcitabine and cisplatin in the treatment of cholangiocarcinoma.
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Hua-Qiang
authors: HQ
authors: Zhu
authors: Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Jin-Ben
authors: JB
authors: Ma
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Xie
authors: X
authors: Song
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Heng-Jun
authors: HJ
authors: Gao
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Chao-Qun
authors: CQ
authors: Ma
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Hong
authors: H
authors: Chang
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Hong-Guang
authors: HG
authors: Li
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Fang-Feng
authors: FF
authors: Liu
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Jun
authors: J
authors: Lu
authors: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.
authors: Xu
authors: X
authors: Zhou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D008687:Metformin; D002945:Cisplatin; D000093542:Gemcitabine