title: Antitumor effects of a combination of interferon-alpha and sorafenib on human renal carcinoma cell lines.
abstract: To support the role of interferon (IFN)-alpha and sorafenib combination therapy against renal cell carcinoma (RCC), the effects of IFN-alpha and sorafenib on tumor growth, vascular endothelial growth factor (VEGF) production, and phosphorylation levels of extracellular signal-regulated kinase (ERK) and mitogen-activated protein/ERK kinase (MEK) were examined using several cultured RCC cell lines (ACHN, Caki-1, Caki-2, SMKT-R1, SMKT-R2, SMKT-R3 and SMKT-R4). IFN-alpha or sorafenib alone inhibited the proliferation of all the cell lines except Caki-2, while combined treatment with the two agents showed enhanced inhibitory effects compared to treatment with each agent alone. VEGF production was inhibited by IFN-alpha alone in ACHN and SMKT-R2 cells and by sorafenib alone in ACHN, Caki-1, SMKT-R1 and SMKT-R2 cells. However, sorafenib increased VEGF production by Caki-2 cells. Interestingly, combined treatment with the two agents suppressed VEGF production by SMKT-R1 and SMKT-R2 cells more strongly than IFN-alpha or sorafenib alone. Although phosphorylated ERK (p-ERK) was increased after 30 min of treatment with IFN-alpha alone, no difference was observed between control and IFN-alpha-treated cells after 2 h. Sorafenib decreased p-ERK in ACHN, Caki-1, SMKT-R1 and SMKT-R2 cells, but increased p-ERK in Caki-2, SMKT-R3 and SMKT-R4 cells, after 2 h. Combined treatment with IFN-alpha and sorafenib decreased p-ERK compared to treatment with each agent alone in all cell lines except Caki-2. However, IFN-alpha did not inhibit the p-ERK increase induced by sorafenib in Caki-2 cells. Phosphorylated MEK showed similar patterns to p-ERK after the various treatments. In conclusion, combined treatment with IFN-alpha and sorafenib suppressed cell proliferation and VEGF production more strongly than treatment with each agent alone in several RCC cell lines.
authors.affiliation: Free Radical Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan. s_tochizawa@research.otsuka.co.jp
authors.forename: Shiro
authors.initials: S
authors.lastname: Tochizawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Masumori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yanai
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Ohmoto
authors.forename: Youichi
authors.initials: Y
authors.lastname: Yabuuchi
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases