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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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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. |
format | Online Article Text |
id | pubmed-6421704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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