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Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. O...

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Autores principales: Xu, Li, Zhu, Yuanrun, Shao, Jinjin, Chen, Min, Yan, Hao, Li, Guanqun, Zhu, Yi, Xu, Zhifei, Yang, Bo, Luo, Peihua, He, Qiaojun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396112/
https://www.ncbi.nlm.nih.gov/pubmed/28267710
http://dx.doi.org/10.1038/bjc.2017.55
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author Xu, Li
Zhu, Yuanrun
Shao, Jinjin
Chen, Min
Yan, Hao
Li, Guanqun
Zhu, Yi
Xu, Zhifei
Yang, Bo
Luo, Peihua
He, Qiaojun
author_facet Xu, Li
Zhu, Yuanrun
Shao, Jinjin
Chen, Min
Yan, Hao
Li, Guanqun
Zhu, Yi
Xu, Zhifei
Yang, Bo
Luo, Peihua
He, Qiaojun
author_sort Xu, Li
collection PubMed
description BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. METHODS: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation. RESULTS: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents. CONCLUSIONS: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy.
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spelling pubmed-53961122017-05-12 Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1 Xu, Li Zhu, Yuanrun Shao, Jinjin Chen, Min Yan, Hao Li, Guanqun Zhu, Yi Xu, Zhifei Yang, Bo Luo, Peihua He, Qiaojun Br J Cancer Translational Therapeutics BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. METHODS: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo. We applied flow cytometry and western blotting to explore the mechanism of the combined therapy. Knockdown and overexpression of PLK1 are also applied for validation. RESULTS: We confirmed that dasatinib has synergistic effect with irinotecan (or SN38) on HCC both in vitro and in vivo. The effect is due to arisen apoptosis rate of HCC cells that is accompanied by mitochondria dysfunction. The enhanced antitumour efficacy of SN38 could be explained by additional inhibition of PLK1, which is triggered by dasatinib. Unlike existed PLK1 inhibitors, dasatinib does not inhibit PLK1 activity in a direct way. Instead, we found that dasatinib reduces PLK1 level by interfering with its protein synthesis progress. We validated that this kind of downregulation of PLK1 level has a key role in the synergistic effect of the two agents. CONCLUSIONS: Dasatinib is able to reinforce the anti-HCC efficacy of irinotecan/SN38 by downregulation of PLK1 synthesis. The combination of the two agents might be a potential medical choice for HCC therapy. Nature Publishing Group 2017-04-11 2017-03-07 /pmc/articles/PMC5396112/ /pubmed/28267710 http://dx.doi.org/10.1038/bjc.2017.55 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Translational Therapeutics
Xu, Li
Zhu, Yuanrun
Shao, Jinjin
Chen, Min
Yan, Hao
Li, Guanqun
Zhu, Yi
Xu, Zhifei
Yang, Bo
Luo, Peihua
He, Qiaojun
Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title_full Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title_fullStr Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title_full_unstemmed Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title_short Dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of PLK1
title_sort dasatinib synergises with irinotecan to suppress hepatocellular carcinoma via inhibiting the protein synthesis of plk1
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396112/
https://www.ncbi.nlm.nih.gov/pubmed/28267710
http://dx.doi.org/10.1038/bjc.2017.55
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