Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody

Authors

  • Kuen-Feng Chen,

    Corresponding author
    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
    2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
    3. School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
    • Correspondence

      Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, no. 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: kfchen1970@ntu.edu.tw

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    • These authors contributed equally to this work.
  • Hui-Ling Chen,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
    2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
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    • These authors contributed equally to this work.
  • Chung-Wai Shiau,

    1. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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    • These authors contributed equally to this work.
  • Chun-Yu Liu,

    1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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  • Pei-Yi Chu,

    1. Department of Pathology, St. Martin De Porres Hospital, Chiayi, Taiwan
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  • Wei-Tien Tai,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
    2. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
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  • Kimihisa Ichikawa,

    1. Group III Oncology Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan
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  • Pei-Jer Chen,

    1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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  • Ann-Lii Cheng

    1. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
    2. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
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Abstract

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.

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