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
Abstract
:1. Introduction
2. Results
2.1. Talazoparib Significantly Inhibits ABCG2- and ABCC1-Mediated Transport of Probe Substrate Drugs
2.2. Talazoparib Is Predicted to Interact with the Ligand-Binding Sites of ABCG2 and ABCC1 and Nucleotide Binding Domain 2 of ABCC1
2.3. Talazoparib Does Not Interfere with the Metabolic Activities of Clinically Relevant CYP Isoforms
2.4. Talazoparib Combats ABCC1- and ABCG2-Mediated Chemotherapeutic Resistance In Vitro
2.5. Talazoparib Targets Cytostatic MDR in Patient-Derived NSCLC Explants Ex Vivo
2.6. MDR-Related Transporters Do Not Establish Resistance to Talazoparib
2.7. Talazoparib Does Not Change the Expressions of MDR-Related Transporters in Breast Cancer Model
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Cell Cultures
4.3. Generation of Primary Explants from Patients’ NSCLC Tissue Samples
4.4. Accumulation Assay with Fluorescent Cytostatic Substrates
4.5. Molecular Docking
4.6. Incubation Assay for Human Recombinant CYPs
4.7. MTT Proliferation Assay
4.8. Drug Combination Assays
4.9. Western Blotting Analysis
4.10. Gene Induction Studies
4.11. Statistical and Data Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cell Line | Drug(s) | IC50 (µM) | 95% CI (µM) | RR |
---|---|---|---|---|
MDCKII-parent | ||||
daunorubicin | 1.00 | (0.878–1.13) | ||
mitoxantrone | 1.48 | (1.35–1.62) | ||
daunorubicin + talazoparib | 1.09 ns | (1.01–1.18) | 0.917 | |
mitoxantrone + talazoparib | 1.40 ns | (1.30–1.53) | 1.06 | |
MDCKII-ABCC1 | ||||
daunorubicin | 5.80 | (5.42–6.19) | ||
daunorubicin + talazoparib | 2.71 ** | (2.36–3.12) | 2.14 | |
MDCKII-ABCG2 | ||||
mitoxantrone | 12.1 | (11.3–12.9) | ||
mitoxantrone + talazoparib | 2.29 *** | (2.04–2.55) | 5.28 | |
A431-parent | ||||
daunorubicin | 1.11 | (0.966–1.29) | ||
mitoxantrone | 0.88 | (0.714–1.06) | ||
daunorubicin + talazoparib | 1.22 ns | (1.05–1.43) | 0.909 | |
mitoxantrone + talazoparib | 0.88 ns | (0.692–1.11) | 1.00 | |
A431-ABCC1 | ||||
daunorubicin | 3.62 | (3.19–4.10) | ||
daunorubicin + talazoparib | 2.13 * | (1.70–2.64) | 1.69 | |
A431-ABCG2 | ||||
mitoxantrone | 10.0 | (9.36–10.7) | ||
mitoxantrone + talazoparib | 3.53 ** | (2.99–4.08) | 2.83 |
Sample No. | Gender | Age | Histopathological Diagnosis |
---|---|---|---|
1 | male | 73 | adenocarcinoma |
2 | male | 66 | squamous carcinoma |
3 | female | 71 | adenocarcinoma |
4 | male | 73 | squamous carcinoma |
5 | male | 72 | adenocarcinoma |
6 | female | 69 | adenocarcinoma |
7 | male | 64 | combined neuroendocrine carcinoma (large cell + small cell) |
8 | male | 70 | squamous carcinoma |
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Sabet, Z.; Vagiannis, D.; Budagaga, Y.; Zhang, Y.; Novotná, E.; Hanke, I.; Rozkoš, T.; Hofman, J. 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. Int. J. Mol. Sci. 2022, 23, 14338. https://doi.org/10.3390/ijms232214338
Sabet Z, Vagiannis D, Budagaga Y, Zhang Y, Novotná E, Hanke I, Rozkoš T, Hofman J. 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. International Journal of Molecular Sciences. 2022; 23(22):14338. https://doi.org/10.3390/ijms232214338
Chicago/Turabian StyleSabet, Ziba, Dimitrios Vagiannis, Youssif Budagaga, Yu Zhang, Eva Novotná, Ivo Hanke, Tomáš Rozkoš, and Jakub Hofman. 2022. "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" International Journal of Molecular Sciences 23, no. 22: 14338. https://doi.org/10.3390/ijms232214338