Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10383092" target="_blank" >RIV/00216208:11160/18:10383092 - isvavai.cz</a>
Result on the web
<a href="http://link.springer.com/article/10.1007/s00204-018-2258-0" target="_blank" >http://link.springer.com/article/10.1007/s00204-018-2258-0</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1007/s00204-018-2258-0" target="_blank" >10.1007/s00204-018-2258-0</a>
Alternative languages
Result language
angličtina
Original language name
Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile
Original language description
Dinaciclib is a multi-specific cyclin-dependent kinase (CDK) inhibitor with significant preclinical and clinical activity. It inhibits CDK1, CDK2, CDK5, CDK9 and CDK12 in the nanomolar range and exhibits potent antiproliferative effects on various cancers in vitro and in vivo. Aldo-keto reductases (AKR) and carbonyl reductases (CBR) are enzymes involved at the biosynthesis, intermediary metabolism and detoxification processes, but can also play a significant role in cancer resistance. Here, we report that dinaciclib is a strong inhibitor of aldo-keto reductase 1C3 (AKR1C3), an enzyme that is known to be an important regulator of cell proliferation and differentiation. AKR1C3 is overexpressed in a range of cancer types and is also involved in tumour cell resistance to anthracyclines. In our study, dinaciclib displayed tight-binding inhibition of human recombinant AKR1C3 (Ki(app) = 0.07 mu M) and was also active at the cellular level (IC50 = 0.23 mu M). Dinaciclib acts as a noncompetitive inhibitor with respect to daunorubicin and as an uncompetitive inhibitor with respect to the NADPH. In subsequent experiments, pretreatment with dinaciclib (0.1 mu M) significantly sensitized AKR1C3-overexpressing anthracycline-resistant cancer cells to daunorubicin. In conclusion, our results indicate that dinaciclib may potentially increase the therapeutic efficacy and safety of anthracyclines by preventing anthracycline resistance and minimizing their adverse effects.
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
2018
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
92
Issue of the periodical within the volume
9
Country of publishing house
DE - GERMANY
Number of pages
13
Pages from-to
2845-2857
UT code for WoS article
000443424300008
EID of the result in the Scopus database
2-s2.0-85049663118