title: Synergy with interferon-lambda 3 and sorafenib suppresses hepatocellular carcinoma proliferation.
abstract: Hepatocellular carcinoma (HCC) is a common and fatal malignancy of the liver. Sorafenib is a small molecule multikinase inhibitor that acts against different cancer cell lines and is used for the treatment of HCC. However, some advanced HCC patients fail to respond to sorafenib, and those who do lack a meaningful clinical benefit. Interferon-lambda 3 (IFN-λ3) is a type III interferon with antiviral, antiproliferative, and immunomodulatory functions. Here, we evaluated the use of IFN-λ3 as an adjuvant treatment with sorafenib in HCC. In the present study, CCK-8 and colony formation assay results showed that treatment with a combination of IFN-λ3 and sorafenib suppresses the viability of HepG2 and SMMC7721 liver cancer cell lines more than treatment with either alone. In addition, flow cytometry results confirmed that treatment with a combination of IFN-λ3 and sorafenib promotes the loss of mitochondrial membrane potential and induces the production of ROS more than treatment with either alone. Furthermore, using a subcutaneous SMMC7721 tumor model, treatment with a combination of IFN-λ3 and sorafenib significantly reduced the tumor growth/volume and induced apoptosis compared to treatment with sorafenib alone. These results show that combined treatment with IFN-λ3 and sorafenib facilitates a synergistic effect on suppressing HCC cancer growth and promoting cell apoptosis in vitro and in vivo. Thus, IFN-λ3 in combination with sorafenib might prove to be a useful adjunctive strategy for the clinical treatment of HCC.
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
authors.forename: Yuke
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: He
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
authors.forename: Yawu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.affiliation: Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China; Division of Liver Disease, Lanzhou University Second Hospital, Lanzhou 730030, PR China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, PR China; Gansu Provincial-Level Key Laboratory of Digestive System Tumors, Lanzhou 730030, PR China. Electronic address: zhangychmd@126.com.
authors.forename: Youcheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077157:Sorafenib; D000095022:Interferon Lambda
chemical_list: D053148:Caspase 3; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007372:Interferons; D007378:Interleukins; D009536:Niacinamide; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D000077157:Sorafenib; C493956:CDKN1A protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
keywords: Apoptosis; Hepatocellular carcinoma; IFN-λ3; Proliferation; Sorafenib; Synergy