Abstract
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.
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Abbreviations
- AKR:
-
Aldo-keto reductase
- CDK:
-
Cyclin-dependent kinase
- CI:
-
Combination index
- CRE:
-
Carbonyl-reducing enzyme
- Dau:
-
Daunorubicin
- Dau-ol:
-
Daunorubicinol
- DOX:
-
Doxorubicin
- DMSO:
-
Dimethyl sulfoxide
- Fa:
-
Fraction affected
- HCT116-AKR1C3:
-
Cells transfected with pCI_AKR1C3
- HCT116-EV:
-
Cells transfected with empty vector pCI
- MTT:
-
3-(4,5-Dimethylthiazoyl-2-yl)2,5-diphenyl tetrazolium bromide
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- PGD2 :
-
Prostaglandin D2
- 11β-PGF2α :
-
9α,11 β-Prostaglandin F2α
- PGH2 :
-
Prostaglandin H2
- PPARγ:
-
Peroxisome proliferator-activated receptor gamma
- SD:
-
Standard deviation
- SDR:
-
Short-chain dehydrogenase/reductase
- UHPLC:
-
Ultra high-performance liquid chromatography
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Acknowledgements
This work was supported by Czech Science Foundation, project no. 16-26849S and by the project EFSA-CDN (no. CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF and finally by Charles University (project no. SVV 260 416). Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures”.
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Novotná, E., Büküm, N., Hofman, J. et al. Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile. Arch Toxicol 92, 2845–2857 (2018). https://doi.org/10.1007/s00204-018-2258-0
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DOI: https://doi.org/10.1007/s00204-018-2258-0