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Talazoparib Does Not Interact with ABCB1 Transporter or Cytochrome P450s, but Modulates Multidrug Resistance Mediated by ABCC1 and ABCG2: An in Vitro and Ex Vivo Study
Z. Sabet, D. Vagiannis, Y. Budagaga, Y. Zhang, E. Novotná, I. Hanke, T. Rozkoš, J. Hofman
Language English Country Switzerland
Document type Journal Article
NLK
Free Medical Journals
from 2000
Freely Accessible Science Journals
from 2000
PubMed Central
from 2007
Europe PubMed Central
from 2007
ProQuest Central
from 2000-03-01
Open Access Digital Library
from 2000-01-01
Open Access Digital Library
from 2007-01-01
Health & Medicine (ProQuest)
from 2000-03-01
ROAD: Directory of Open Access Scholarly Resources
from 2000
PubMed
36430819
DOI
10.3390/ijms232214338
Knihovny.cz E-resources
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics MeSH
- ATP-Binding Cassette Transporters genetics metabolism MeSH
- Humans MeSH
- Drug Resistance, Multiple MeSH
- Neoplasm Proteins metabolism MeSH
- Lung Neoplasms * MeSH
- Carcinoma, Non-Small-Cell Lung * drug therapy genetics MeSH
- ATP Binding Cassette Transporter, Subfamily B genetics MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Talazoparib (Talzenna) is a novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is clinically used for the therapy of breast cancer. Furthermore, the drug has shown antitumor activity against different cancer types, including non-small cell lung cancer (NSCLC). In this work, we investigated the possible inhibitory interactions of talazoparib toward selected ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs) and evaluated its position in multidrug resistance (MDR). In accumulation studies, talazoparib interacted with the ABCC1 and ABCG2 transporters, but there were no significant effects on ABCB1. Furthermore, incubation assays revealed a negligible capacity of the tested drug to inhibit clinically relevant CYPs. In in vitro drug combination experiments, talazoparib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCC1 and ABCG2 expression, respectively. Importantly, the position of an effective MDR modulator was further confirmed in drug combinations performed in ex vivo NSCLC patients-derived explants, whereas the possible victim role was refuted in comparative proliferation experiments. In addition, talazoparib had no significant effects on the mRNA-level expressions of MDR-related ABC transporters in the MCF-7 cellular model. In summary, our study presents a comprehensive overview on the pharmacokinetic drug-drug interactions (DDI) profile of talazoparib. Moreover, we introduced talazoparib as an efficient MDR antagonist.
References provided by Crossref.org
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