title: A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3.
abstract: Radiotherapy shows limited benefit as treatment for hepatocellular carcinoma (HCC). In this study, we aimed to overcome the radioresistance of HCC by using a novel sorafenib derivative, SC-59 that targets SHP-1-related signaling. HCC cell lines (SK-Hep1, Hep3B, and Huh7) were treated with sorafenib, SC-59, radiation, sorafenib plus radiation, or SC-59 plus radiation, and then apoptosis, colony formation, signal transduction and the phosphatase activity were analyzed. The synergistic effect of radiotherapy and SC-59 was analyzed using a combination index (CI) approach. In vivo efficacy was determined in a Huh7-bearing subcutaneous model. Mice were treated with radiation (5 Gy, one fraction per day) for 4 days, SC-59 (10mg/kg/day) for 24 days, or a combination. Tumor samples were further analyzed for p-STAT3 and SHP-1 activity. SC-59 displayed a better synergistic effect when used in combination with radiotherapy than sorafenib in HCC cell lines. SC-59 downregulated p-STAT3 and its downstream targets and increased SHP-1 phosphatase activity. Both ectopic STAT3 and inhibition of SHP-1 abolished SC-59-induced radiosensitization. Moreover, SC-59 significantly synergized radiotherapy in a Huh7 xenograft model by targeting SHP-1/STAT3 signaling. The novel sorafenib derivative, SC-59, acting as a SHP-1 agonist, displays a better synergistic effect when used in combination with radiotherapy than sorafenib for the treatment of HCC. Further clinical investigation is warranted.
authors.affiliation: Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Radiological Technology, Yuanpei University, Hsinchu, Taiwan.
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wan-Mai
authors.initials: WM
authors.lastname: Hsu
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ying-Jiun
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan. Electronic address: cwshiau@ym.edu.tw.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; C581705:SC-59 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
keywords: Apoptosis; HCC; Radiation; SC-59; SHP-1