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Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression

Authors Zhang W, Zhou H, Yu Y, Li J, Li H, Jiang D, Chen Z, Yang D, Xu Z, Yu Z

Received 20 November 2015

Accepted for publication 5 April 2016

Published 2 June 2016 Volume 2016:9 Pages 3359—3368

DOI https://doi.org/10.2147/OTT.S100936

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Manfred Beleut

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati


Wendian Zhang,* Hechao Zhou,* Ying Yu,* Jingjing Li, Haiwen Li, Danxian Jiang, Zihong Chen, Donghong Yang, Zumin Xu, Zhonghua Yu

Cancer Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province, People’s Republic of China

*These authors contributed equally to this work

Abstract: Cisplatin resistance is a main clinical problem of lung cancer therapy. Gambogic acid (GA) could prohibit the proliferation of a variety of human cancer cells. However, the effects of GA on cisplatin-resistant lung cancer are still unclear. The objective of the present study was to find out the antitumor effects of GA on cisplatin-resistant human lung cancer A549/DDP cells and further explore its underlying mechanisms. Cell Counting Kit-8 assay was used to observe the impacts of GA and/or cisplatin on the proliferation of lung cancer cells; flow cytometry was used to detect the effects of GA on cell cycle and apoptosis; Western blot was used to examine the effects of GA on the expression of lung resistance protein (LRP) and multidrug resistance-associated protein 2 (MRP2) protein in A549/DDP cells. Our results showed that GA dose- and time-dependently prohibited the proliferation and induced significant cell apoptosis in A549 and A549/DDP cells. GA also induced G0/G1 arrest in both A549/DDP and A549 cells. Moreover, GA upregulated protein expression level of cleaved caspase-3 and Bax and downregulated protein expression level of pro-caspase-9 and Bcl-2 in time- and dose-dependent way in A549/DDP cells. GA combined with cisplatin enhanced the cells apoptotic rate and reduced the cisplatin resistance index in A549/DDP cells. In addition, GA reduced the MRP2 and LRP protein expression level in A549/DDP cells. GA inhibits the proliferation, induces cell cycle arrest and apoptosis in A549/DDP cells. Combination of GA with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression.

Keywords: gambogic acid, cisplatin, drug resistance, lung cancer, lung resistance protein, multidrug resistance-associated protein 2, anti-tumor, cell cycle arrest, cell apoptosis

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