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Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase

BACKGROUND: Urokinase (uPA) and its receptor (uPAR) play an important role in tumour growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Targeting the excessive activation of this system as well as the proliferati...

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Autores principales: Lin, Yuli, Peng, Nana, Li, Jianping, Zhuang, Hongqin, Hua, Zi-Chun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728221/
https://www.ncbi.nlm.nih.gov/pubmed/23758884
http://dx.doi.org/10.1186/1476-4598-12-54
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author Lin, Yuli
Peng, Nana
Li, Jianping
Zhuang, Hongqin
Hua, Zi-Chun
author_facet Lin, Yuli
Peng, Nana
Li, Jianping
Zhuang, Hongqin
Hua, Zi-Chun
author_sort Lin, Yuli
collection PubMed
description BACKGROUND: Urokinase (uPA) and its receptor (uPAR) play an important role in tumour growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Targeting the excessive activation of this system as well as the proliferation of the tumour vascular endothelial cell would be expected to prevent tumour neovasculature and halt tumour development. The amino terminal fragment (ATF) of urokinase has been confirmed effective to inhibit the proliferation, migration and invasiveness of cancer cells via interrupting the interaction of uPA and uPAR. Triptolide (TPL) is a purified diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic anticancer activity of TPL and ATF in various solid tumour cells. METHODS: Using in vitro and in vivo experiments, we investigated the combined effect of TPL and ATF at a low dosage on cell proliferation, cell apoptosis, cell cycle distribution, cell migration, signalling pathways, xenograft tumour growth and angiogenesis. RESULTS: Our data showed that the sensitivity of a combined therapy using TPL and ATF was higher than that of TPL or ATF alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle arrest, and inhibition of uPAR-mediated signalling pathway contributed to the synergistic effects of this combination therapy. Furthermore, using a mouse xenograft model, we demonstrated that the combined treatment completely suppressed tumour growth by inhibiting angiogenesis as compared with ATF or TPL treatment alone. CONCLUSIONS: Our study suggests that lower concentration of ATF and TPL used in combination may produce a synergistic anticancer efficacy that warrants further investigation for its potential clinical applications.
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spelling pubmed-37282212013-08-01 Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase Lin, Yuli Peng, Nana Li, Jianping Zhuang, Hongqin Hua, Zi-Chun Mol Cancer Research BACKGROUND: Urokinase (uPA) and its receptor (uPAR) play an important role in tumour growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumours. Targeting the excessive activation of this system as well as the proliferation of the tumour vascular endothelial cell would be expected to prevent tumour neovasculature and halt tumour development. The amino terminal fragment (ATF) of urokinase has been confirmed effective to inhibit the proliferation, migration and invasiveness of cancer cells via interrupting the interaction of uPA and uPAR. Triptolide (TPL) is a purified diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic anticancer activity of TPL and ATF in various solid tumour cells. METHODS: Using in vitro and in vivo experiments, we investigated the combined effect of TPL and ATF at a low dosage on cell proliferation, cell apoptosis, cell cycle distribution, cell migration, signalling pathways, xenograft tumour growth and angiogenesis. RESULTS: Our data showed that the sensitivity of a combined therapy using TPL and ATF was higher than that of TPL or ATF alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle arrest, and inhibition of uPAR-mediated signalling pathway contributed to the synergistic effects of this combination therapy. Furthermore, using a mouse xenograft model, we demonstrated that the combined treatment completely suppressed tumour growth by inhibiting angiogenesis as compared with ATF or TPL treatment alone. CONCLUSIONS: Our study suggests that lower concentration of ATF and TPL used in combination may produce a synergistic anticancer efficacy that warrants further investigation for its potential clinical applications. BioMed Central 2013-06-08 /pmc/articles/PMC3728221/ /pubmed/23758884 http://dx.doi.org/10.1186/1476-4598-12-54 Text en Copyright © 2013 Lin et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Lin, Yuli
Peng, Nana
Li, Jianping
Zhuang, Hongqin
Hua, Zi-Chun
Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title_full Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title_fullStr Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title_full_unstemmed Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title_short Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
title_sort herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728221/
https://www.ncbi.nlm.nih.gov/pubmed/23758884
http://dx.doi.org/10.1186/1476-4598-12-54
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