Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F20%3A10417502" target="_blank" >RIV/00216208:11160/20:10417502 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=FrX~J1KYaC" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=FrX~J1KYaC</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bcp.2020.114061" target="_blank" >10.1016/j.bcp.2020.114061</a>
Alternative languages
Result language
angličtina
Original language name
Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme
Original language description
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 approximate to CYP3A4 > CYP2C9 > CYP2C19 approximate to 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochemical Pharmacology
ISSN
0006-2952
e-ISSN
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Volume of the periodical
178
Issue of the periodical within the volume
August
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
114061
UT code for WoS article
000551658300023
EID of the result in the Scopus database
2-s2.0-85086605020