ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo

Yanfen Fang; Juanjuan Sun; Xing Zhong; Rui Hu; Jie Gao; Guanfu Duan; Changge Ji; Lijuan Chen; Wanli Zhang; Chunxiao Miao; Haji Akber Aisa; Xiongwen Zhang

doi:10.1016/j.phrs.2017.11.001

ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo

Pharmacol Res. 2018 Mar:129:388-399. doi: 10.1016/j.phrs.2017.11.001. Epub 2017 Nov 7.

Authors

Yanfen Fang¹, Juanjuan Sun², Xing Zhong³, Rui Hu⁴, Jie Gao⁴, Guanfu Duan³, Changge Ji³, Lijuan Chen³, Wanli Zhang³, Chunxiao Miao³, Haji Akber Aisa⁵, Xiongwen Zhang⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China; Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China; State Key Laboratory of Cell Biology, Center of Excellence in Molecular and Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
⁴ The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China.
⁵ The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China. Electronic address: [email protected].
⁶ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China. Electronic address: [email protected].

PMID: 29122696
DOI: 10.1016/j.phrs.2017.11.001

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.

Keywords: ABCB1; Chemotherapeutic agents; Jatrophane diterpenoid ester; MDR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B / metabolism
Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Diterpenes / pharmacology*
Diterpenes / therapeutic use
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Esters / pharmacology*
Esters / therapeutic use
Female
Humans
Mice, Inbred BALB C
Mice, Nude

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
Diterpenes
Esters