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Archives of Toxicology

, Volume 92, Issue 9, pp 2845–2857 | Cite as

Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile

  • Eva Novotná
  • Neslihan Büküm
  • Jakub Hofman
  • Michaela Flaxová
  • Etela Kouklíková
  • Dagmar Louvarová
  • Vladimír Wsól
Molecular Toxicology

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.

Keywords

Dinaciclib Anthracyclines AKR1C3 Multidrug resistance Cancer 

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-PGF

9α,11 β-Prostaglandin F

PGH2

Prostaglandin H2

PPARγ

Peroxisome proliferator-activated receptor gamma

SD

Standard deviation

SDR

Short-chain dehydrogenase/reductase

UHPLC

Ultra high-performance liquid chromatography

Notes

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”.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

204_2018_2258_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1153 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemical Sciences, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic
  2. 2.Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec KrálovéCharles UniversityHradec KrálovéCzech Republic

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