Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
32497550
DOI
10.1016/j.bcp.2020.114061
PII: S0006-2952(20)30295-1
Knihovny.cz E-resources
- Keywords
- ABC transporter, Cytochrome P450, Drug interaction, Entrectinib, Multidrug resistance, Non-small cell lung cancer,
- MeSH
- Benzamides pharmacology MeSH
- A549 Cells MeSH
- Hep G2 Cells MeSH
- Madin Darby Canine Kidney Cells MeSH
- Drug Resistance, Neoplasm drug effects physiology MeSH
- Cytochrome P-450 CYP3A * chemistry metabolism MeSH
- Cytostatic Agents pharmacology MeSH
- Indazoles pharmacology MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Humans MeSH
- Drug Resistance, Multiple drug effects physiology MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors chemistry metabolism MeSH
- Dogs MeSH
- Protein Structure, Secondary MeSH
- Molecular Docking Simulation methods MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ABCB1 protein, human MeSH Browser
- Benzamides MeSH
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A * MeSH
- Cytostatic Agents MeSH
- entrectinib MeSH Browser
- Indazoles MeSH
- Protein Kinase Inhibitors MeSH
- ATP Binding Cassette Transporter, Subfamily B MeSH
Entrectinib is a new tyrosine kinase inhibitor that was recently approved for the treatment of ROS1-positive metastatic non-small cell lung cancer (NSCLC). In this study, we aimed to characterize its potential to act as a modulator of pharmacokinetic cytostatic resistance and perpetrator of drug interactions. In accumulation studies, entrectinib exhibited potent inhibition of ABCB1, while only moderate interaction was recorded for ABCG2 and ABCC1 efflux transporters. Furthermore, incubation assays revealed the potential of this drug to inhibit various recombinant cytochrome P450 enzymes, which can be ranked according to inhibitory affinities as follows: CYP2C8 ≈ CYP3A4 > CYP2C9 > CYP2C19 ≈ CYP3A5 > CYP2D6 > CYP2B6 > CYP1A2. Additionally, in silico docking analysis confirmed entrectinib's interactions with ABCB1 and CYP3A4 and resolved their possible molecular background. In subsequent drug combination experiments, we demonstrated the ability of entrectinib to synergize with daunorubicin in various ABCB1-expressing cellular models. Moreover, the comparative proliferation study results suggested that the anticancer efficacy of entrectinib is not affected by the functional presence of tested ABC transporters. In contrast to ABCB1-related data, no resistance reversal effect was recorded for the combination with docetaxel in HepG2-CYP3A4 cells. In the final experimental set, we observed no significant changes in ABCB1, ABCG2, ABCC1 or CYP3A4 gene expression in NSCLC cells exposed to entrectinib. In summary, our work indicates that entrectinib may be a perpetrator of clinically relevant pharmacokinetic drug interactions and modulator of ABCB1-mediated resistance. Our in vitro results might provide a valuable foundation for future clinical investigations.
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