These authors contributed equally to this work.
Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody
Article first published online: 16 JAN 2013
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Volume 168, Issue 3, pages 658–672, February 2013
How to Cite
Chen, K.-F., Chen, H.-L., Shiau, C.-W., Liu, C.-Y., Chu, P.-Y., Tai, W.-T., Ichikawa, K., Chen, P.-J. and Cheng, A.-L. (2013), Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody. British Journal of Pharmacology, 168: 658–672. doi: 10.1111/j.1476-5381.2012.02212.x
- Issue published online: 16 JAN 2013
- Article first published online: 16 JAN 2013
- Accepted manuscript online: 17 SEP 2012 04:27AM EST
- Manuscript Accepted: 10 AUG 2012
- Manuscript Revised: 13 JUL 2012
- Manuscript Received: 24 NOV 2011
- National Taiwan University Hospital. Grant Number: NTUH 100P04
- National Science Council, Taiwan. Grant Numbers: NSC99-2314-B-002-017-MY2, NSC 100-3112-B-002 -013, NSC 100-2325-B-002 -036, NSC 100-2325-B-010 -007
- Taiwan Clinical Oncology Research Foundation
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.
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.
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.