Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels.

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F17%3A73585352" target="_blank" >RIV/61989592:15110/17:73585352 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0009279717300352?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0009279717300352?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.cbi.2017.06.012" target="_blank" >10.1016/j.cbi.2017.06.012</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels.

Popis výsledku v původním jazyce

Recently, it has been suggested that imatinib (IM) and nilotinib (NIL) could be studied beyond their original application, as inhibitors of the drug efflux pump ABCB1 (P-glycoprotein, MDR1). Since the reversal of ABCB1-mediated resistance has never been successfully demonstrated in the clinic, we addressed the question of whether IM and NIL may actually serve as efficient inhibitors of ABCB1. Here we define an efficient inhibitor as a compound that achieves full (90–100%) reversal of drug efflux at a concentration that does not exhibit significant off-target toxicity in vitro. In this study, human leukemia K562 cells expressing various levels of ABCB1 were used. We observed that cells expressing higher ABCB1 levels required higher concentrations of IM and NIL to achieve full reversal of drug efflux. Among the well-known ABCB1 inhibitors, a similar effect was found for cyclosporin A (CsA) but not for zosuquidar. IM was efficient only in cells with the low and moderate ABCB1 expression at high concentrations that were cytotoxic in the absence of Bcr-Abl. In contrast, NIL was as efficient an inhibitor of ABCB1 as CsA. Low and moderate expression levels of ABCB1 could be efficiently inhibited by NIL concentrations without cytotoxic effects in the absence of Bcr-Abl. However, high expression levels of ABCB1 required higher NIL concentrations with off-target cytotoxic effects. In conclusion, application of NIL, but not of IM, in clinics is promising, however, only in cells with low ABCB1 expression levels. We hypothesize that some patients may benefit from an inhibitor exhibiting an ABCB1 expression-dependent effect.

Název v anglickém jazyce

Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels.

Popis výsledku anglicky

Recently, it has been suggested that imatinib (IM) and nilotinib (NIL) could be studied beyond their original application, as inhibitors of the drug efflux pump ABCB1 (P-glycoprotein, MDR1). Since the reversal of ABCB1-mediated resistance has never been successfully demonstrated in the clinic, we addressed the question of whether IM and NIL may actually serve as efficient inhibitors of ABCB1. Here we define an efficient inhibitor as a compound that achieves full (90–100%) reversal of drug efflux at a concentration that does not exhibit significant off-target toxicity in vitro. In this study, human leukemia K562 cells expressing various levels of ABCB1 were used. We observed that cells expressing higher ABCB1 levels required higher concentrations of IM and NIL to achieve full reversal of drug efflux. Among the well-known ABCB1 inhibitors, a similar effect was found for cyclosporin A (CsA) but not for zosuquidar. IM was efficient only in cells with the low and moderate ABCB1 expression at high concentrations that were cytotoxic in the absence of Bcr-Abl. In contrast, NIL was as efficient an inhibitor of ABCB1 as CsA. Low and moderate expression levels of ABCB1 could be efficiently inhibited by NIL concentrations without cytotoxic effects in the absence of Bcr-Abl. However, high expression levels of ABCB1 required higher NIL concentrations with off-target cytotoxic effects. In conclusion, application of NIL, but not of IM, in clinics is promising, however, only in cells with low ABCB1 expression levels. We hypothesize that some patients may benefit from an inhibitor exhibiting an ABCB1 expression-dependent effect.

Druh

J_SC - Článek v periodiku v databázi SCOPUS

CEP obor

—

OECD FORD obor

10609 - Biochemical research methods

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Chemico-Biological Interactions

ISSN

0009-2797

e-ISSN

—

Svazek periodika

273

Číslo periodika v rámci svazku

May 2017

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

9

Strana od-do

171-179

Kód UT WoS článku

000406467500019

EID výsledku v databázi Scopus

2-s2.0-85021146577