CMP25, a synthetic new agent, targets multidrug resistance-associated protein 7 (MRP7/ABCC10)

Jing-Quan Wang; Bo Wang; Qiu-Xu Teng; Zi-Ning Lei; Yi-Dong Li; Zhi Shi; Li-Ying Ma; Hong-Min Liu; Zhijun Liu; Zhe-Sheng Chen

doi:10.1016/j.bcp.2021.114652

CMP25, a synthetic new agent, targets multidrug resistance-associated protein 7 (MRP7/ABCC10)

Biochem Pharmacol. 2021 Aug:190:114652. doi: 10.1016/j.bcp.2021.114652. Epub 2021 Jun 11.

Authors

Jing-Quan Wang¹, Bo Wang², Qiu-Xu Teng¹, Zi-Ning Lei¹, Yi-Dong Li¹, Zhi Shi³, Li-Ying Ma², Hong-Min Liu⁴, Zhijun Liu⁵, Zhe-Sheng Chen⁶

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
² Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
³ Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, PR China.
⁴ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.
⁵ Department of Medical Microbiology, Weifang Medical University, Weifang 261053, PR China. Electronic address: zhijun.liu@wfmc.edu.cn.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: chenz@stjohns.edu.

PMID: 34126072
DOI: 10.1016/j.bcp.2021.114652

Abstract

Multidrug resistance-associated protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to mediate the cross-membrane translocation of a wide range of chemotherapeutic agents including taxanes, epothilones, Vinca alkaloids, Anthracyclines and Epipodophyllotoxins.In our previous study, a 1,2,3-triazole-pyrimidine hybridCMP25was synthesized and found able to efficiently reverse multidrug resistance (MDR) mediated by P-glycoprotein. In this study, we evaluated the efficacy of compound CMP25in reversing MDR mediated by MRP7in vitro. The results showed that CMP25significantly sensitized MRP7-overexpressing cells to anticancer drugs that are MRP7 substrates. Mechanistic study showed that CMP25reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or subcellular localization. Currently, very few studies on synthetic MRP7 modulators have been published. Our findings provide a valuable prototype for designing drugs to combine with conventional anticancer drugs to overcome MDR-mediated by MRP7.

Keywords: 1,2,3-Triazole-pyrimidine hybrid; ABC transporters; ABCC10; MRP7; Multidrug resistance.

Publication types

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

MeSH terms

Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Survival / drug effects*
Drug Delivery Systems
Drug Resistance, Neoplasm / drug effects*
Drug Therapy, Combination
Gene Expression Regulation / drug effects
HEK293 Cells
Humans
Models, Molecular
Molecular Dynamics Simulation
Molecular Structure
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Multidrug Resistance-Associated Proteins / genetics
Multidrug Resistance-Associated Proteins / metabolism*
Protein Conformation

Substances

ABCC10 protein, human
Antineoplastic Agents
Multidrug Resistance-Associated Proteins