title: Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil cells.
abstract: Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Sunbin
authors.initials: S
authors.lastname: Ling
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Jia
authors.affiliation: Department of Intergrative Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Deguang
authors.initials: D
authors.lastname: Sun
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Gao
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D018435:ATP Binding Cassette Transporter, Subfamily B; D005472:Fluorouracil; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008687:Metformin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D058570:TOR Serine-Threonine Kinases; C497442:HIF1A protein, human; C546842:MTOR protein, human; C421109:multidrug resistance-associated protein 1