Clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F17%3A73585423" target="_blank" >RIV/61989592:15110/17:73585423 - isvavai.cz</a>

Result on the web

<a href="https://www.ingentaconnect.com/contentone/govi/pharmaz/2017/00000072/00000012/art00008" target="_blank" >https://www.ingentaconnect.com/contentone/govi/pharmaz/2017/00000072/00000012/art00008</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1691/ph.2017.7696" target="_blank" >10.1691/ph.2017.7696</a>

Result language

angličtina

Original language name

Clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters

Original language description

In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT-199 below the control level in parental cells. Our results further revealed that ABT-263 did not inhibit the ABCB1 mediated transport, however, it partially inhibited the ABCG2 mediated transport at clinically relevant concentrations. In contrast, ABT-199 inhibited partially the ABCB1 mediated transport and it fully inhibited the ABCG2 mediated transport at clinically relevant concentrations. Importantly, cells expressing higher drug transporters levels required higher concentrations of ABT-263 or ABT-199 to achieve certain inhibition of substrate efflux. CONCLUSIONS: Antiproliferative effects of ABT-263 and ABT-199 might be reduced by ABCB1 or ABCG2, however, this effect depends on transporter expression levels. Since the expression levels of ABCB1 and ABCG2 are rarely high in clinical samples, their contribution to the overall resistance to ABT-263 or ABT-199 is probably low. Inhibition study revealed that ABT-199, but not ABT-263, fully inhibited low expression level of ABCG2. Our data suggest that ABT-199 should be evaluated beyond its original application as an inhibitor of the ABCG2 transporter in clinical settings.

Czech name

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Czech description

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Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

—

OECD FORD branch

10609 - Biochemical research methods

Project

—

Continuities

S - Specificky vyzkum na vysokych skolach

Publication year

2017

Confidentiality

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

Name of the periodical

PHARMAZIE

ISSN

0031-7144

e-ISSN

—

Volume of the periodical

72

Issue of the periodical within the volume

12

Country of publishing house

DE - GERMANY

Number of pages

8

Pages from-to

751-758

UT code for WoS article

000426406700008

EID of the result in the Scopus database

2-s2.0-85038812640