Chen K.-F.Chen H.-L.Shiau C.-W.Liu C.-Y.Chu P.-Y.Tai W.-T.Ichikawa K.PEI-JER CHENANN-LII CHENG2021-07-032021-07-0320130007-1188https://www.scopus.com/inward/record.uri?eid=2-s2.0-84984558781&doi=10.1111%2fj.1476-5381.2012.02212.x&partnerID=40&md5=ff866b4ef1ae171654301e4fda5e7c4ehttps://scholars.lib.ntu.edu.tw/handle/123456789/568475Background 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.[SDGs]SDG3angiogenesis 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 xenograftjournal article10.1111/j.1476-5381.2012.02212.x2-s2.0-84984558781