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Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor.

Authors :
Teng, Qiu-Xu
Lei, Zi-Ning
Wang, Jing-Quan
Yang, Yuqi
Wu, Zhuo-Xun
Acharekar, Nikita Dilip
Zhang, Wei
Yoganathan, Sabesan
Pan, Yihang
Wurpel, John
Chen, Zhe-Sheng
Fang, Shuo
Source :
Drug Resistance Updates; Mar2024, Vol. 73, pN.PAG-N.PAG, 1p
Publication Year :
2024

Abstract

The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
13687646
Volume :
73
Database :
Supplemental Index
Journal :
Drug Resistance Updates
Publication Type :
Academic Journal
Accession number :
175833605
Full Text :
https://doi.org/10.1016/j.drup.2023.101028