Wei-Tien Tai1, Chung-Wai Shiau2, Yong-Shi Li1, Chun-Wei Chang1, Jui-Wen Huang3, Ting-Ting Hsueh2, Hui-Chuan Yu1, Kuen-Feng Chen4. 1. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. 2. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. 3. Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsin-Chu, Taiwan. 4. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan; National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: kfchen1970@ntu.edu.tw.
Abstract
BACKGROUND & AIMS: Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect. METHODS: To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n⩾8 mice). RESULTS: Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3. CONCLUSIONS: Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib.
BACKGROUND & AIMS:Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect. METHODS: To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n⩾8 mice). RESULTS:Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3. CONCLUSIONS:Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib.
Authors: Niranjan Awasthi; Stefan Hinz; Rolf A Brekken; Margaret A Schwarz; Roderich E Schwarz Journal: Cancer Lett Date: 2014-12-16 Impact factor: 8.679
Authors: Massimiliano Berretta; Luca Rinaldi; Fabrizio Di Benedetto; Arben Lleshi; Vallì De Re; Gaetano Facchini; Paolo De Paoli; Raffaele Di Francia Journal: Front Pharmacol Date: 2016-11-09 Impact factor: 5.810