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

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 potentia...

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Autores principales: Luo, Teng, Zhang, Shou-Guo, Zhu, Ling-Fei, Zhang, Fei-Xiang, Li, Wei, Zhao, Ke, Wen, Xiao-Xue, Yu, Miao, Zhan, Yi-Qun, Chen, Hui, Ge, Chang-Hui, Gao, Hui-Ying, Wang, Lin, Yang, Xiao-Ming, Li, Chang-Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421704/
https://www.ncbi.nlm.nih.gov/pubmed/30885237
http://dx.doi.org/10.1186/s13046-019-1104-4
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author Luo, Teng
Zhang, Shou-Guo
Zhu, Ling-Fei
Zhang, Fei-Xiang
Li, Wei
Zhao, Ke
Wen, Xiao-Xue
Yu, Miao
Zhan, Yi-Qun
Chen, Hui
Ge, Chang-Hui
Gao, Hui-Ying
Wang, Lin
Yang, Xiao-Ming
Li, Chang-Yan
author_facet Luo, Teng
Zhang, Shou-Guo
Zhu, Ling-Fei
Zhang, Fei-Xiang
Li, Wei
Zhao, Ke
Wen, Xiao-Xue
Yu, Miao
Zhan, Yi-Qun
Chen, Hui
Ge, Chang-Hui
Gao, Hui-Ying
Wang, Lin
Yang, Xiao-Ming
Li, Chang-Yan
author_sort Luo, Teng
collection PubMed
description 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.
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spelling pubmed-64217042019-03-28 A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth Luo, Teng Zhang, Shou-Guo Zhu, Ling-Fei Zhang, Fei-Xiang Li, Wei Zhao, Ke Wen, Xiao-Xue Yu, Miao Zhan, Yi-Qun Chen, Hui Ge, Chang-Hui Gao, Hui-Ying Wang, Lin Yang, Xiao-Ming Li, Chang-Yan J Exp Clin Cancer Res Research 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. BioMed Central 2019-03-18 /pmc/articles/PMC6421704/ /pubmed/30885237 http://dx.doi.org/10.1186/s13046-019-1104-4 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Luo, Teng
Zhang, Shou-Guo
Zhu, Ling-Fei
Zhang, Fei-Xiang
Li, Wei
Zhao, Ke
Wen, Xiao-Xue
Yu, Miao
Zhan, Yi-Qun
Chen, Hui
Ge, Chang-Hui
Gao, Hui-Ying
Wang, Lin
Yang, Xiao-Ming
Li, Chang-Yan
A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title_full A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title_fullStr A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title_full_unstemmed A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title_short A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth
title_sort selective c-met and trks inhibitor indo5 suppresses hepatocellular carcinoma growth
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421704/
https://www.ncbi.nlm.nih.gov/pubmed/30885237
http://dx.doi.org/10.1186/s13046-019-1104-4
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