Tirabrutinib-anthracycline interactions in the brain tumor microenvironment: a focus on metabolic inactivation and resistance

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10509886" target="_blank" >RIV/00216208:11160/25:10509886 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_g7jsL2m0r" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=_g7jsL2m0r</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1080/17425255.2025.2595661" target="_blank" >10.1080/17425255.2025.2595661</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Tirabrutinib-anthracycline interactions in the brain tumor microenvironment: a focus on metabolic inactivation and resistance

Popis výsledku v původním jazyce

Background: Anthracyclines (ANTs) remain essential in many anticancer regimens, yet their clinical utility is often limited by multidrug resistance. Recent studies suggest that Bruton&apos;s tyrosine kinase inhibitors (BTKis) may enhance the efficacy of ANT-based therapies, including those targeting brain tumors. This study investigates how tirabrutinib may contribute to such enhancement via interactions with aldo-keto reductase 1C3 (AKR1C3) and ABC efflux transporters. Research design and methods: The inhibitory potential of tirabrutinib was evaluated using recombinant enzymes, transiently transfected HCT116 cells, and cell lines with differential AKR1C3 expression (T98G, MRC-5). ABC transporter-expressing cells were used to assess daunorubicin accumulation. Western blotting was used to examine whether tirabrutinib alters AKR1C3 protein expression. Results:Tirabrutinib inhibited daunorubicin metabolism in both recombinant AKR1C3 assays and AKR1C3-expressing cells, but had no effect in non-expressing cells. It also enhanced intracellular accumulation of daunorubicin in relevant models. No significant changes in AKR1C3 expression were observed following tirabrutinib treatment. Conclusions: Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways. However, Chou-Talalay analysis highlights the importance of appropriate dosing to achieve therapeutic synergy in combination regimens.

Název v anglickém jazyce

Tirabrutinib-anthracycline interactions in the brain tumor microenvironment: a focus on metabolic inactivation and resistance

Popis výsledku anglicky

Background: Anthracyclines (ANTs) remain essential in many anticancer regimens, yet their clinical utility is often limited by multidrug resistance. Recent studies suggest that Bruton&apos;s tyrosine kinase inhibitors (BTKis) may enhance the efficacy of ANT-based therapies, including those targeting brain tumors. This study investigates how tirabrutinib may contribute to such enhancement via interactions with aldo-keto reductase 1C3 (AKR1C3) and ABC efflux transporters. Research design and methods: The inhibitory potential of tirabrutinib was evaluated using recombinant enzymes, transiently transfected HCT116 cells, and cell lines with differential AKR1C3 expression (T98G, MRC-5). ABC transporter-expressing cells were used to assess daunorubicin accumulation. Western blotting was used to examine whether tirabrutinib alters AKR1C3 protein expression. Results:Tirabrutinib inhibited daunorubicin metabolism in both recombinant AKR1C3 assays and AKR1C3-expressing cells, but had no effect in non-expressing cells. It also enhanced intracellular accumulation of daunorubicin in relevant models. No significant changes in AKR1C3 expression were observed following tirabrutinib treatment. Conclusions: Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways. However, Chou-Talalay analysis highlights the importance of appropriate dosing to achieve therapeutic synergy in combination regimens.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EH22_008%2F0004607" target="_blank" >EH22_008/0004607: Nové technologie pro translační výzkum ve farmaceutických vědách /NETPHARM</a><br>

Návaznosti

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

Rok uplatnění

2025

Kód důvěrnosti údajů

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

Název periodika

Expert Opinion on Drug Metabolism &amp; Toxicology

ISSN

1742-5255

e-ISSN

1744-7607

Svazek periodika

21

Číslo periodika v rámci svazku

11-12

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

12

Strana od-do

1315-1326

Kód UT WoS článku

001629080100001

EID výsledku v databázi Scopus

2-s2.0-105023706658