Biological evaluation of non-basic chalcone CYB-2 as a dual ABCG2/ABCB1 inhibitor.

Abstract

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.

• Authors: Chao-Yun Cai, Wei Zhang, Jing-Quan Wang, Zi-Ning Lei, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Cai-Ping Tan, Bo Wang, Zhe-Sheng Chen
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 175 Pg. 113848 (05 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32044354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Antineoplastic Agents
• Chalcones
• Neoplasm Proteins

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, genetics)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (antagonists & inhibitors, genetics)
• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Chalcones (chemistry, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Molecular Docking Simulation
• Neoplasm Proteins (antagonists & inhibitors, genetics)