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A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth

Authors :
Ke Zhao
Wen Xiaoxue
Miao Yu
Yi-Qun Zhan
Hui Chen
Wei Li
Ling-Fei Zhu
Fei-Xiang Zhang
Lin Wang
Chang-Yan Li
Chang-Hui Ge
Teng Luo
Hui-Ying Gao
Shou-Guo Zhang
Xiao-Ming Yang
Source :
Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-13 (2019), Journal of Experimental & Clinical Cancer Research : CR
Publication Year :
2019
Publisher :
BMC, 2019.

Abstract

Background Human hepatocellular carcinoma (HCC) lacks effective curative therapy and there is an urgent need to develop a novel molecular-targeted therapy for HCC. Selective tyrosine kinase inhibitors have shown promise in treating cancers including HCC. Tyrosine kinases c-Met and Trks are potential therapeutic targets of HCC and strategies to interrupt c-Met and Trks cross-signaling may result in increased effects on HCC inhibition. Methods The effects of Indo5 on c-Met and Trks activity were determined with in vitro kinase activity assay, cell-based signaling pathway activation, and kinases-driven cell transformation. The in vivo anti-tumor activity was determined with xenograft mice and liver orthotopic mice models. The co-expression of c-Met and TrkB in 180 pairs of HCC and adjacent normal tissues were detected using immunohistochemical staining. Results Indo5, a novel lead compound displayed biochemical potency against both c-Met and Trks with selectivity over 13 human kinases. Indo5 abrogated HGF-induced c-Met signaling activation and BDNF/NGF-induced Trks signal activation, c-Met or TrkB-mediated cell transformation and migration. Furthermore, Indo5 significantly decreased the growth of HCC cells in xenograft mice and improved the survival of mice with liver orthotopic tumors. In addition, co-expression of c-Met and TrkB in HCC patients was a predictor of poor prognosis, and combined inhibition of c-Met and TrkB exerted a synergistic suppressive effect on HCC. Conclusions These findings indicate that Indo5 is associated with marked suppression of c-Met and Trks co-expressing HCC, supporting its clinical development as an antitumor treatment for HCC patients with co-active c-Met and Trks signaling. Electronic supplementary material The online version of this article (10.1186/s13046-019-1104-4) contains supplementary material, which is available to authorized users.

Details

Language :
English
ISSN :
17569966
Volume :
38
Issue :
1
Database :
OpenAIRE
Journal :
Journal of Experimental & Clinical Cancer Research
Accession number :
edsair.doi.dedup.....1ee7c268e9d2bf8802982c01793b1f65