title: Sorafenib and TRAIL have synergistic effect on hepatocellular carcinoma.
abstract: A multi-kinase inhibitor, sorafenib, was recently approved and is currently             recommended for the treatment of advanced hepatocellular carcinoma (HCC). However,             HCC treatment outcomes are still poor and necessitate improvement. Therefore,             we investigated the influence of sorafenib in combination with each of cytotoxic             chemotherapy agents, hypoxia or tumor necrosis factor (TNF)-related apoptosis‑inducing             ligand (TRAIL), on cytotoxicity to determine which is the better adjuvant. Additive             cytotoxicity of sorafenib to chemotherapy agents, hypoxia and TRAIL, to HCC cells             was assessed using cell viability assay. Intracellular levels of anti-apoptotic             proteins were determined using western blot analysis. Activation of Wnt/β-catenin             signaling was assessed using a luciferase reporter gene assay. Sorafenib significantly             and synergistically enhanced the cytotoxicity of TRAIL to HCC cells and 4',6-diamidino-2-phenylindole             (DAPI) staining showed increased apoptosis among cells treated with sorafenib             and TRAIL. This augmentation in cytotoxicity was derived from sorafenib-mediated             downregulation of anti-apoptotic proteins. However, sorafenib did not enhance             the cytotoxicity of chemotherapy agents (cisplatin, 5-FU or doxorubicin) or hypoxic             treatment to HCC. Moreover, hypoxic treatment induced Wnt/β-catenin signaling             activation. Our data showed that in combination TRAIL and sorafenib had a synergistic             cytokilling effect on HCC cells and that this effect derived from sorafenib-mediated             downregulation of anti-apoptotic proteins.
authors.affiliation: First Department of Internal Medicine, Mie University School                     of Medicine, Tsu, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Nojiri
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shiraki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tameda
authors.forename: Yuuji
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Suguru
authors.initials: S
authors.lastname: Ogura
authors.forename: Chika
authors.initials: C
authors.lastname: Kasai
authors.forename: Satoko
authors.initials: S
authors.lastname: Kusagawa
authors.forename: Misao
authors.initials: M
authors.lastname: Yoneda
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nobori
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004357:Drug Synergism; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; D009536:Niacinamide; D000077157:Sorafenib