Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity

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• 作者：Wei-Tien Tai¹ ; ² ; ^&dagger ; ; Chung-Wai Shiau³ ; ^&dagger ; ; Yong-Shi Li¹ ; ² ; Chun-Wei Chang¹ ; ² ; Jui-Wen Huang⁴ ; Ting-Ting Hsueh³ ; Hui-Chuan Yu¹ ; ² ; Kuen-Feng Chen¹ ; ² ; ^{kfchen1970@ntu.edu.tw" class="auth_mail}
• 关键词：HCC ; hepatocellular carcinoma ; Ab ; antibody ; IP ; immunoprecipitation ; p-STAT3 ; phosphorylated STAT3 ; PTPs ; protein tyrosine phosphatases ; SH2 ; Src homology region 2 ; SHP-1 ; SH2 domain-containing phosphatase 1 ; STAT3 ; signal transducer and activator of transcription 3 ; VEGF ; vascular endothelial growth factor receptor ; VEGFR ; vascular endothelial growth factor receptor ; WT ; wild type
• 刊名：Journal of Hepatology
• 出版年：July 2014
• 年：2014
• 卷：61
• 期：1
• 页码：89-97
• 全文大小：2021 K

文摘

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, 螖N. HCC cell lines were treated with nintedanib or its derivative (螖N) 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 猢?#xA0;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 螖N only retained the backbone of nintedanib without kinase activity, 螖N 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.