کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6103104 | 1211123 | 2014 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Research ArticleNintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity Research ArticleNintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity](/preview/png/6103104.png)
Background & AimsNintedanib, 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.MethodsTo 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, ÎN. HCC cell lines were treated with nintedanib or its derivative (ÎN) 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).ResultsNintedanib 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 ÎN only retained the backbone of nintedanib without kinase activity, ÎN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3.ConclusionsNintedanib 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.
Journal: Journal of Hepatology - Volume 61, Issue 1, July 2014, Pages 89-97