Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines.
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.
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China.
Sunbin
S
Ling
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Tingting
T
Feng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, P.R. China.
Qinghong
Q
Ke
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Ning
N
Fan
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Lei
L
Li
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China.
Zhongxing
Z
Li
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China.
Chengyong
C
Dong
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Cong
C
Wang
College of Basic Medical Sciences, Dalian Medical University, Dalian, P.R. China.
Fei
F
Xu
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, P.R. China.
Yan
Y
Li
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, P.R. China.
Liming
L
Wang
D000091162:AMP-Activated Protein Kinase Kinases; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000008:administration & dosage*; D046912:Multiprotein Complexes / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D046912:Multiprotein Complexes; D008687:Metformin; D011494:Protein Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases