https://scholars.lib.ntu.edu.tw/handle/123456789/568475
標題: | Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody | 作者: | Chen K.-F. Chen H.-L. Shiau C.-W. Liu C.-Y. Chu P.-Y. Tai W.-T. Ichikawa K. PEI-JER CHEN ANN-LII CHENG |
公開日期: | 2013 | 出版社: | John Wiley and Sons Inc. | 卷: | 168 | 期: | 3 | 起(迄)頁: | 658-672 | 來源出版物: | British Journal of Pharmacology | 摘要: | Background and Purpose: Previously, we have shown that sorafenib sensitizes hepatocellular carcinoma (HCC) to apoptosis induced by TNF-related apoptosis-inducing ligand (TNFSF10; TRAIL). Here, we report that sorafenib and SC-49 sensitize HCC cells to CS-1008, a novel anti-human death receptor 5 (TNFRSF10B) antibody. Experimental Approach: HCC cell lines (PLC5, Huh-7, and Hep3B) were treated with CS-1008 and/or sorafenib and analysed in terms of apoptosis and signal transductions. Key Results: SC-49 is a sorafenib derivative, which is devoid of kinase inhibitory activity. Both sorafenib and SC-49 down-regulated the phosphorylation of STAT3 at Tyr705 and subsequently reduced the levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in CS-1008-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to CS-1008 in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effects of sorafenib and SC-49 on CS-1008-induced apoptosis, indicating that inhibition of STAT3 mediates the enhancing effects of these compounds when combined with CS-1008. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and CS-1008 on p-STAT3 and apoptosis, whereas co-treatment of CS-1008 with SC-49 increased the activity of SHP-1. These data indicate that the combined effects of CS-1008 and SC-49 on HCC are mediated by SHP-1. Moreover, the combination of CS-1008 and SC-49 inhibited HCC xenograft tumour growth in vivo. Conclusions and Implications: Sorafenib and its derivative SC-49 sensitize HCC cells to the antitumour effects of CS-1008 through SHP-1-dependent inactivation of STAT3. British Journal of Pharmacology ? 2012 The British Pharmacological Society. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984558781&doi=10.1111%2fj.1476-5381.2012.02212.x&partnerID=40&md5=ff866b4ef1ae171654301e4fda5e7c4e https://scholars.lib.ntu.edu.tw/handle/123456789/568475 |
ISSN: | 0007-1188 | DOI: | 10.1111/j.1476-5381.2012.02212.x | SDG/關鍵字: | angiogenesis inhibitor; cyclin D1; protein mcl 1; protein tyrosine phosphatase SHP 1; scandium 49; sorafenib; STAT3 protein; survivin; tigatuzumab; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer cell culture; cancer inhibition; carcinoma cell; concentration response; controlled study; down regulation; drug potentiation; drug resistance; drug sensitization; enzyme activity; enzyme inhibition; in vitro study; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein expression; protein phosphorylation; signal transduction; tumor xenograft |
顯示於: | 臨床醫學研究所 |
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