ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo. (March 2018)

• Record Type: Journal Article
• Authors: Fang, Yanfen; Sun, Juanjuan; Zhong, Xing; Hu, Rui; Gao, Jie; Duan, Guanfu; Ji, Changge; Chen, Lijuan; Zhang, Wanli; Miao, Chunxiao; Aisa, Haji Akber; Zhang, Xiongwen
• Is Part Of: Pharmacological research. Volume 129(2018)
• Page Start: 388
• Page End: 399
• Publication Date: 2018-03
• Subjects: MDR multidrug resistance -- ABCB1 ATP-binding cassette subfamily B member 1 -- ABC ATP binding cassette -- P-gp P-glycoprotein -- Rho123 rhodamine-123 -- NVB Vinorelbine -- PTX paclitaxel -- DOX doxorubicin -- DDP cisplatin -- TPT topotecan -- VPL Verapamil -- FTC Fumitremorgin C -- RLU relative light units -- RTV relative tumor volume -- TGI tumor growth inhibition; MDR -- ABCB1 -- Jatrophane diterpenoid ester -- Chemotherapeutic agents; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2017.11.001
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: ES2 is a new type of jatrophane diterpenoid ester isolated from the fructus E. sororia, a traditional Uyghur medicine in China. Here we reported the multidrug resistance (MDR) reversal effect of ES2 in vitro and in vivo by modulating the function of ATP-binding cassette subfamily B member 1 (ABCB1). ES2 exhibited low cytotoxicity to ABCB1-overexpressing MDR cells and their parental sensitive cells, but sensitized the MDR cells and ABCB1-transfected HEK293 cells to chemotherapeutic drugs that are ABCB1 substrates. The reversal ability of ES2 was primarily due to the inhibition of the efflux function of ABCB1. Moreover, ES2 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. There was no change in the expression of ABCB1 in the presence of ES2. The molecular docking analysis indicated that ES2 bond to the drug-binding site of ABCB1 transporter. Importantly, ES2 significantly enhanced the anti-tumor effect of vinorelbine against KBv200 cell xenografts in nude mice. Overall, these findings demonstrate that ES2 inhibits the ABCB1 transporter function and consequently reverses ABCB1-mediated MDR, indicating the potential use of ES2 in combination therapy with conventional chemotherapeutic drugs for cancer treatment.