title: Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway.
abstract: The multi‑kinase inhibitor sorafenib is the only drug for which randomized control trials have shown improved patient survival in advanced hepatocellular carcinoma (HCC). However, life expectancy is extended in these cases by only a few months. The anti‑type II diabetes agent metformin was used in this study in an effort to find a more efficient approach to HCC treatment. Sorafenib effectively reversed the activation status of mTORC2 induced by metformin and enhanced the suppression of the mTORC1 and MAPK pathway by metformin in HCC cells, which may be responsible for reduced proliferation upon combined treatment. The metformin and sorafenib combination led to increased impaired proliferation and tumor inhibition of HCC in vitro and in vivo compared to single agent, which was partially bridged by disrupting the mTORC1/mTORC2 feedback loop. Metformin and sorafenib cooperated to promote apoptosis and autophagy in HCC cells. Pharmacological inhibition of autophagy sensitized HCC cells to metformin and sorefenib‑induced apoptotic cell death. Therefore, the anti‑autophagy treatment should be considered in metformin and sorafenib-based treatments in HCC cells.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 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: The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Fan
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: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, 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: Feng
authors.initials: F
authors.lastname: Zhao
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
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: 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: College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
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
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008687:Metformin / Q000008:administration & dosage*; D046912:Multiprotein Complexes / Q000187:drug effects; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D046912:Multiprotein Complexes; D010671:Phenylurea Compounds; D009536:Niacinamide; D008687:Metformin; D000077157:Sorafenib; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases