Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile
Language English Country Germany Media print-electronic
Document type Journal Article
PubMed
29992508
DOI
10.1007/s00204-018-2258-0
PII: 10.1007/s00204-018-2258-0
Knihovny.cz E-resources
- Keywords
- AKR1C3, Anthracyclines, Cancer, Dinaciclib, Multidrug resistance,
- MeSH
- Anthracyclines administration & dosage MeSH
- Bridged Bicyclo Compounds, Heterocyclic administration & dosage pharmacology MeSH
- Hep G2 Cells MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Cyclic N-Oxides MeSH
- Daunorubicin metabolism pharmacokinetics MeSH
- HCT116 Cells MeSH
- Indolizines MeSH
- Enzyme Inhibitors pharmacology MeSH
- Humans MeSH
- Aldo-Keto Reductase Family 1 Member C3 antagonists & inhibitors genetics metabolism MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Pyridinium Compounds administration & dosage pharmacology MeSH
- Gene Expression Regulation, Enzymologic drug effects MeSH
- Recombinant Proteins genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- AKR1C3 protein, human MeSH Browser
- Anthracyclines MeSH
- Bridged Bicyclo Compounds, Heterocyclic MeSH
- Cyclic N-Oxides MeSH
- Daunorubicin MeSH
- dinaciclib MeSH Browser
- Indolizines MeSH
- Enzyme Inhibitors MeSH
- Aldo-Keto Reductase Family 1 Member C3 MeSH
- Pyridinium Compounds MeSH
- Recombinant Proteins MeSH
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 (Kiapp = 0.07 µM) and was also active at the cellular level (IC50 = 0.23 µM). 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 µM) 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.
References provided by Crossref.org
Olaparib Synergizes the Anticancer Activity of Daunorubicin via Interaction with AKR1C3
Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors
