Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Interactions of antileukemic drugs with daunorubicin reductases: could reductases affect the clinical efficacy of daunorubicin chemoregimens?
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - 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
Result continuities
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)
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Archives of Toxicology
ISSN
0340-5761
e-ISSN
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Volume of the periodical
94
Issue of the periodical within the volume
9
Country of publishing house
DE - GERMANY
Number of pages
10
Pages from-to
3059-3068
UT code for WoS article
000543307900003
EID of the result in the Scopus database
2-s2.0-85087089548