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

Molecular Cancer

Research

Yuli Lin¹  Nana Peng¹  Jianping Li¹  Hongqin Zhuang²  Zi-Chun Hua² 

[1] The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, 22 Han Kou Road, 210093, Nanjing, PR China;The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, 22 Han Kou Road, 210093, Nanjing, PR China;Changzhou High-Tech Research Institute of Nanjing University, 213164, Changzhou, Jiangsu, PR China;Jiangsu TargetPharma Laboratories Inc., 213164, Changzhou, Jiangsu, PR China;

关键词: Amino-terminal fragment of urokinase;    Triptolide;    Synergism;    Apoptosis;    Cell migration;    Cell cycle;    Xenograft;   

DOI  :  10.1186/1476-4598-12-54

 received in 2013-02-21, accepted in 2013-06-05,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundUrokinase (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.MethodsUsing 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.ResultsOur 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Lin et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. 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.