title: Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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 Tyr(705)  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
  Sorafenib and its derivative SC-49 sensitize HCC cells to the antitumour effects of CS-1008 through SHP-1-dependent inactivation of STAT3.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Kimihisa
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C581982:SC-49 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C505639:TNFRSF10B protein, human; C552861:tigatuzumab; D009536:Niacinamide; D000077157:Sorafenib