https://scholars.lib.ntu.edu.tw/handle/123456789/584717
標題: | A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3 | 作者: | CHAO YUAN HUANG Tai, Wei-Tien Hsieh, Chi-Ying Hsu, Wan-Mai Lai, Ying-Jiun Chen, Li-Ju Shiau, Chung-Wai Chen, Kuen-Feng |
關鍵字: | Apoptosis; HCC; Radiation; SC-59; SHP-1 | 公開日期: | 28-七月-2014 | 卷: | 349 | 期: | 2 | 來源出版物: | Cancer letters | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/584717 | ISSN: | 03043835 | DOI: | 10.1016/j.canlet.2014.04.006 | SDG/關鍵字: | antineoplastic agent; phosphatase; phosphoprotein; protein tyrosine phosphatase SHP 1; sc 59; sorafenib; STAT3 protein; unclassified drug; antineoplastic agent; carbanilamide derivative; protein kinase inhibitor; protein tyrosine phosphatase SHP 1; PTPN6 protein, human; radiosensitizing agent; SC-59 compound; STAT3 protein; STAT3 protein, human; animal experiment; animal model; antineoplastic activity; apoptosis; article; cancer cell culture; cancer radiotherapy; chemoradiotherapy; colony formation; down regulation; drug efficacy; drug potentiation; drug targeting; enzyme activity; enzyme inhibition; Hep3B cell line; histopathology; Huh7 cell; human; human cell; in vitro study; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; radiation dose; radiosensitivity; radiosensitization; signal transduction; SK Hep1 cell line; treatment duration; tumor model; tumor xenograft; animal; antagonists and inhibitors; Carcinoma, Hepatocellular; drug effects; drug potentiation; drug screening; genetic transfection; genetics; Liver Neoplasms; metabolism; multimodality cancer therapy; nude mouse; pathology; radiation response; randomization; tumor cell line; Mus; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Combined Modality Therapy; Drug Synergism; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Radiation-Sensitizing Agents; Random Allocation; Signal Transduction; STAT3 Transcription Factor; Transfection; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
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