Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme
Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters...
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/4/813 |
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| author | Dimitrios Vagiannis Eva Novotna Adam Skarka Sarah Kammerer Jan-Heiner Küpper Si Chen Lei Guo Frantisek Staud Jakub Hofman |
| author_facet | Dimitrios Vagiannis Eva Novotna Adam Skarka Sarah Kammerer Jan-Heiner Küpper Si Chen Lei Guo Frantisek Staud Jakub Hofman |
| author_sort | Dimitrios Vagiannis |
| collection | DOAJ |
| description | Ensartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib’s antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations. |
| first_indexed | 2024-03-11T10:11:25Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T10:11:25Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fef5d9851add4eca95afe35e3e748c5f2023-11-16T14:32:39ZengMDPI AGCancers2072-66942020-03-0112481310.3390/cancers12040813Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation EnzymeDimitrios Vagiannis0Eva Novotna1Adam Skarka2Sarah Kammerer3Jan-Heiner Küpper4Si Chen5Lei Guo6Frantisek Staud7Jakub Hofman8Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech RepublicDepartment of Chemistry, Faculty of Science, University of Hradec Králové, Hradecká 1285, 500 03 Hradec Králové, Czech RepublicInstitute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz 1, 01968 Senftenberg, GermanyInstitute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz 1, 01968 Senftenberg, GermanyDivision of Biochemical Toxicology, National Center for Toxicological Research/U.S. FDA, 3900 NCTR Road, Jefferson, AR 72079, USADivision of Biochemical Toxicology, National Center for Toxicological Research/U.S. FDA, 3900 NCTR Road, Jefferson, AR 72079, USADepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech RepublicEnsartinib (X-396) is a promising tyrosine kinase inhibitor currently undergoing advanced clinical evaluation for the treatment of non-small cell lung cancer. In this work, we investigate possible interactions of this promising drug candidate with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs), which play major roles in multidrug resistance (MDR) and pharmacokinetic drug-drug interactions (DDIs). Accumulation studies showed that ensartinib is a potent inhibitor of ABCB1 and ABCG2 transporters. Additionally, incubation experiments with recombinant CYPs showed that ensartinib significantly inhibits CYP3A4 and CYP2C9. Subsequent molecular docking studies confirmed these findings. Drug combination experiments demonstrated that ensartinib synergistically potentiates the antiproliferative effects of daunorubicin, mitoxantrone, and docetaxel in ABCB1, ABCG2, and CYP3A4-overexpressing cellular models, respectively. Advantageously, ensartinib’s antitumor efficiency was not compromised by the presence of MDR-associated ABC transporters, although it acted as a substrate of ABCB1 in Madin-Darby Canine Kidney II (MDCKII) monolayer transport assays. Finally, we demonstrated that ensartinib had no significant effect on the mRNA-level expression of examined transporters and enzymes in physiological and lung tumor cellular models. In conclusion, ensartinib may perpetrate clinically relevant pharmacokinetic DDIs and modulate ABCB1-, ABCG2-, and CYP3A4-mediated MDR. The in vitro findings presented here will provide a valuable foundation for future in vivo investigations.https://www.mdpi.com/2072-6694/12/4/813ensartinibcancermultidrug resistancedrug-drug interactionABC transportercytochrome P450 |
| spellingShingle | Dimitrios Vagiannis Eva Novotna Adam Skarka Sarah Kammerer Jan-Heiner Küpper Si Chen Lei Guo Frantisek Staud Jakub Hofman Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme Cancers ensartinib cancer multidrug resistance drug-drug interaction ABC transporter cytochrome P450 |
| title | Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme |
| title_full | Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme |
| title_fullStr | Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme |
| title_full_unstemmed | Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme |
| title_short | Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme |
| title_sort | ensartinib x 396 effectively modulates pharmacokinetic resistance mediated by abcb1 and abcg2 drug efflux transporters and cyp3a4 biotransformation enzyme |
| topic | ensartinib cancer multidrug resistance drug-drug interaction ABC transporter cytochrome P450 |
| url | https://www.mdpi.com/2072-6694/12/4/813 |
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