Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F20%3A10417721" target="_blank" >RIV/00216208:11160/20:10417721 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PP4-3oJXcP" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PP4-3oJXcP</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00204-020-02818-y" target="_blank" >10.1007/s00204-020-02818-y</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?

Popis výsledku v původním jazyce

Although novel anticancer drugs are being developed intensively, anthracyclines remain the gold standard in the treatment of acute myeloid leukaemia (AML). The reductive conversion of daunorubicin (Dau) to less active daunorubicinol (Dau-ol) is an important mechanism that contributes to the development of pharmacokinetic anthracycline resistance. Dau is a key component in many AML regimes, in which it is combined with many drugs, including all-trans-retinoic acid (ATRA), cytarabine, cladribine and prednisolone. In the present study, we investigated the influence of these anticancer drugs on the reductive Dau metabolism mediated by the aldo-keto reductases AKR1A1, 1B10, 1C3, and 7A2 and carbonyl reductase 1 (CBR1). In incubation experiments with recombinant enzymes, cladribine and cytarabine did not significantly inhibit the activity of the tested enzymes. Prednisolone inhibited AKR1C3 with an IC(50) of 41.73 mu M, while ATRA decreased the activity of AKR1B10 (IC50 = 78.33 mu M) and AKR1C3 (IC50 = 1.17 mu M). Subsequent studies showed that AKR1C3 inhibition mediated by ATRA exhibited tight binding (Ki(app) = 0.54 mu M). Further, the combination of 1 mu M ATRA with different concentrations of Dau demonstrated synergistic effects in HCT116 and KG1a human cells expressing AKR1C3. Our results suggest that ATRA-mediated inhibition of AKR1C3 can contribute to the mechanisms that are hidden beyond the beneficial clinical outcome of the ATRA-Dau combination.

Název v anglickém jazyce

Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?

Popis výsledku anglicky

Although novel anticancer drugs are being developed intensively, anthracyclines remain the gold standard in the treatment of acute myeloid leukaemia (AML). The reductive conversion of daunorubicin (Dau) to less active daunorubicinol (Dau-ol) is an important mechanism that contributes to the development of pharmacokinetic anthracycline resistance. Dau is a key component in many AML regimes, in which it is combined with many drugs, including all-trans-retinoic acid (ATRA), cytarabine, cladribine and prednisolone. In the present study, we investigated the influence of these anticancer drugs on the reductive Dau metabolism mediated by the aldo-keto reductases AKR1A1, 1B10, 1C3, and 7A2 and carbonyl reductase 1 (CBR1). In incubation experiments with recombinant enzymes, cladribine and cytarabine did not significantly inhibit the activity of the tested enzymes. Prednisolone inhibited AKR1C3 with an IC(50) of 41.73 mu M, while ATRA decreased the activity of AKR1B10 (IC50 = 78.33 mu M) and AKR1C3 (IC50 = 1.17 mu M). Subsequent studies showed that AKR1C3 inhibition mediated by ATRA exhibited tight binding (Ki(app) = 0.54 mu M). Further, the combination of 1 mu M ATRA with different concentrations of Dau demonstrated synergistic effects in HCT116 and KG1a human cells expressing AKR1C3. Our results suggest that ATRA-mediated inhibition of AKR1C3 can contribute to the mechanisms that are hidden beyond the beneficial clinical outcome of the ATRA-Dau combination.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Archives of Toxicology

ISSN

0340-5761

e-ISSN

—

Svazek periodika

94

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

10

Strana od-do

3059-3068

Kód UT WoS článku

000543307900003

EID výsledku v databázi Scopus

2-s2.0-85087089548