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J Exp Clin Cancer Res. 2019 Mar 18;38(1):130. doi: 10.1186/s13046-019-1104-4.

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

Author information

1
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
2
Beijing Institute of Radiation Medicine, 27-Taiping Road, Beijing, 100850, People's Republic of China.
3
Institute of NBC Defence, Beijing, 102205, China.
4
An Hui Medical University, Hefei, 230032, China.
5
Guangdong pharmaceutical university, School of Pharmacy, Guangzhou, 510006, China.
6
Beijing Institute of Radiation Medicine, 27-Taiping Road, Beijing, 100850, People's Republic of China. wanglin07@sina.com.
7
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. xiaomingyang@sina.com.
8
School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin University, Tianjin, 300072, China. xiaomingyang@sina.com.
9
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. fmmli@163.com.
10
An Hui Medical University, Hefei, 230032, China. fmmli@163.com.
11
Guangdong pharmaceutical university, School of Pharmacy, Guangzhou, 510006, China. fmmli@163.com.

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.

KEYWORDS:

C-met; Hepatocellular carcinoma; Specific inhibitor; Therapeutic strategy; TrkB

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