Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme

Popis výsledku v původním jazyce

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 &gt; CYP2C9 &gt; CYP2C19 approximate to CYP3A5 &gt; CYP2D6 &gt; CYP2B6 &gt; CYP1A2. Additionally, in silico docking analysis confirmed entrectinib&apos;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.

Název v anglickém jazyce

Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme

Popis výsledku anglicky

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 &gt; CYP2C9 &gt; CYP2C19 approximate to CYP3A5 &gt; CYP2D6 &gt; CYP2B6 &gt; CYP1A2. Additionally, in silico docking analysis confirmed entrectinib&apos;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochemical Pharmacology

ISSN

0006-2952

e-ISSN

—

Svazek periodika

178

Číslo periodika v rámci svazku

August

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

114061

Kód UT WoS článku

000551658300023

EID výsledku v databázi Scopus

2-s2.0-85086605020