Bruton's Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F22%3A10451090" target="_blank" >RIV/00216208:11160/22:10451090 - isvavai.cz</a>

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=K2yxVtC7f~" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=K2yxVtC7f~</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/pharmaceutics14101994" target="_blank" >10.3390/pharmaceutics14101994</a>

Result language

angličtina

Original language name

Bruton's Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux

Original language description

Zanubrutinib (ZAN) is a Bruton&apos;s tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to treatment discontinuation. This study showed that ZAN counteracts ANT resistance by targeting aldo-keto reductase 1C3 (AKR1C3) and ATP-binding cassette (ABC) transporters. AKR1C3 catalyses the transformation of ANTs to less potent hydroxy-metabolites, whereas transporters decrease the ANT-effective concentrations by pumping them out of the cancer cells. In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. In the drug combination experiments, ZAN synergistically sensitised AKR1C3-expressing HCT116 and A549 cells to DAUN treatment. Gene induction studies further confirmed that ZAN did not increase the intracellular level of AKR1C3 mRNA; thus, the drug combination effect is not abolished by enzyme induction. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters.

Czech name

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Czech description

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Type

J_imp - 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

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)

Publication year

2022

Confidentiality

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

Name of the periodical

Pharmaceutics

ISSN

1999-4923

e-ISSN

—

Volume of the periodical

14

Issue of the periodical within the volume

10

Country of publishing house

CH - SWITZERLAND

Number of pages

16

Pages from-to

1994

UT code for WoS article

000873469500001

EID of the result in the Scopus database

2-s2.0-85140972090