Bruton's Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F20%3A10423531" target="_blank" >RIV/00216208:11160/20:10423531 - isvavai.cz</a>

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Wkz5dKVXie" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=Wkz5dKVXie</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers12123731" target="_blank" >10.3390/cancers12123731</a>

Result language

angličtina

Original language name

Bruton's Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

Original language description

The enzyme aldo-keto reductase 1C3 (AKR1C3) is present in several cancers, in which it is capable of actively metabolising different chemotherapy drugs and decreasing their cytotoxic effects. Therefore, the combination with specific inhibitors of AKR1C3 might prevent drug metabolism and increase its efficacy. We investigated the ability of Bruton&apos;s tyrosine kinase inhibitors ibrutinib and acalabrutinib to block the AKR1C3 mediated inactivation of the anthracycline daunorubicin. Experimentation with recombinant AKR1C3 and different cancer cells expressing this enzyme outlined BTK-inhibitors as potential partners to synergise daunorubicin cytotoxicity in vitro. This evidence could be useful to improve the clinical outcome of anthracycline-based chemotherapies. Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton&apos;s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.

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

<a href="/en/project/EF16_019%2F0000841" target="_blank" >EF16_019/0000841: Efficiency and safety improvement of current drugs and nutraceuticals: advanced methods - new challenges</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

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

Name of the periodical

Cancers

ISSN

2072-6694

e-ISSN

—

Volume of the periodical

12

Issue of the periodical within the volume

12

Country of publishing house

CH - SWITZERLAND

Number of pages

17

Pages from-to

3731

UT code for WoS article

000601803400001

EID of the result in the Scopus database

2-s2.0-85097838261