Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články
PubMed
29992508
DOI
10.1007/s00204-018-2258-0
PII: 10.1007/s00204-018-2258-0
Knihovny.cz E-zdroje
- Klíčová slova
- AKR1C3, Anthracyclines, Cancer, Dinaciclib, Multidrug resistance,
- MeSH
- antracykliny aplikace a dávkování MeSH
- bicyklické sloučeniny heterocyklické aplikace a dávkování farmakologie MeSH
- buňky Hep G2 MeSH
- chemorezistence účinky léků MeSH
- cyklické N-oxidy MeSH
- daunomycin metabolismus farmakokinetika MeSH
- HCT116 buňky MeSH
- indoliziny MeSH
- inhibitory enzymů farmakologie MeSH
- lidé MeSH
- protein AKR1C3 antagonisté a inhibitory genetika metabolismus MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie MeSH
- pyridinové sloučeniny aplikace a dávkování farmakologie MeSH
- regulace genové exprese enzymů účinky léků MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AKR1C3 protein, human MeSH Prohlížeč
- antracykliny MeSH
- bicyklické sloučeniny heterocyklické MeSH
- cyklické N-oxidy MeSH
- daunomycin MeSH
- dinaciclib MeSH Prohlížeč
- indoliziny MeSH
- inhibitory enzymů MeSH
- protein AKR1C3 MeSH
- pyridinové sloučeniny MeSH
- rekombinantní proteiny 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.
Citace poskytuje Crossref.org
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