Abstract
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.
Funder
Grant Agency of Charles University
Czech Science Foundation
Charles University
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference67 articles.
1. Combined treatment of non-small cell lung cancer using radiotherapy and immunotherapy: Challenges and updates;Cancer Commun.,2021
2. Epidemiology of lung cancer;Contemp. Oncol.,2021
3. International lung cancer trends by histologic type: Male: Female differences diminishing and adenocarcinoma rates rising;Int. J. Cancer,2005
4. Huang, C.-Y., Ju, D.-T., Chang, C.-F., Reddy, P.M., and Velmurugan, B.K. (2017). A review on the effects of current chemotherapy drugs and natural agents in treating non–small cell lung cancer. Biomedicine, 7.
5. Targeted cancer therapy: The next generation of cancer treatment;Curr. Drug Discov. Technol.,2015
Cited by
8 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献