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Sorafenib and its derivative SC ‐49 sensitize hepatocellular carcinoma cells to CS ‐1008, a humanized anti‐TNFRSF10B (DR 5) antibody
Author(s) -
Chen KuenFeng,
Chen HuiLing,
Shiau ChungWai,
Liu ChunYu,
Chu PeiYi,
Tai WeiTien,
Ichikawa Kimihisa,
Chen PeiJer,
Cheng AnnLii
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02212.x
Subject(s) - sorafenib , apoptosis , cancer research , gene knockdown , hepatocellular carcinoma , stat3 , survivin , chemistry , cell growth , medicine , biochemistry
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 ( PLC 5, H uh‐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 T yr 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 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 .