Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor.
Drug Resist Updat
; 73: 101028, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38340425
ABSTRACT
AIMS:
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.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
/
Ftalazinas
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Drug Resist Updat
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos