Cisplatin is one of the first-line drugs for urothelial bladder cancer (UBC) treatment. However, its considerable side effects and the emergence of drug resistance are becoming major limitations for its application. This study aimed to investigate whether matrine and cisplatin could present a synergistic anti-tumor effect on UBC cells.
Cell viability assay was used to assess the suppressive effect of matrine and cisplatin on the proliferation of the UBC cells. Wound healing assay and transwell assay were applied respectively to determine the migration and invasion ability of the cells. The distribution of cell cycles, the generation of reactive oxygen species (ROS) and the apoptosis rate were detected by flow cytometry (FCM). The expressions of the relative proteins in apoptotic signal pathways and the epithelial-mesenchymal transition (EMT) related genes were surveyed by western blotting. The binding modes of the drugs within the proteins were detected by CDOCKER module in DS 2.5.
Both matrine and cisplatin could inhibit the growth of the UBC cells in a time- and dose-dependent manner. When matrine combined with cisplatin at the ratio of 2000:1, they presented a synergistic inhibitory effect on the UBC cells. The combinative treatment could impair cell migration and invasion ability, arrest cell cycle in the G1 and S phases, increase the level of ROS, and induce apoptosis in EJ and T24 cells in a synergistic way. In all the treated groups, the expressions of E-cadherin, β-catenin, Bax, and Cleaved Caspase-3 were up-regulated, while the expressions of Fibronectin, Vimentin, Bcl-2, Caspase-3, p-Akt, p-PI3K, VEGFR2, and VEGF proteins were down-regulated, and among them, the combination of matrine and cisplatin showed the most significant difference. Molecular docking algorithms predicted that matrine and cisplatin could be docked into the same active sites and interact with different residues within the tested proteins.
Our results suggested that the combination of matrine and cisplatin could synergistically inhibit the UBC cells' proliferation through down-regulating VEGF/PI3K/Akt signaling pathway, indicating that matrine may serve as a new option in the combinative therapy in the treatment of UBC.
Cancer cell international. 2017 Dec 28*** epublish ***
Xiao-Zhong Liao, Lan-Ting Tao, Jia-Hui Liu, Yue-Yu Gu, Jun Xie, Yuling Chen, Mei-Gui Lin, Tao-Li Liu, Dong-Mei Wang, Hai-Yan Guo, Sui-Lin Mo
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 People's Republic of China., The Second Clinical College, Guangzhou University of Chinese Medicine and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120 People's Republic of China., Peking Union Medical College Hospital, Peking Union Medical College, China Academy of Medical Sciences, Beijing, 100730 People's Republic of China., Sydney Acupuncture & Chinese Medicine Centre, Hurstville, NSW 2220 Australia., Liwan District Shi wei tang Street Community Health Service Center, Guangzhou, 510360 People's Republic of China., The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107 People's Republic of China., School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006 People's Republic of China., Graduate School of China Academy of Chinese Medical Sciences, Beijing, 100700 People's Republic of China.