Abstract
Midostaurin is an FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor that provides renewed hope for treating acute myeloid leukaemia (AML). The limited efficacy of this compound as a monotherapy contrasts with that of its synergistic combination with standard cytarabine and daunorubicin (Dau), suggesting a therapeutic benefit that is not driven only by FLT3 inhibition. In an AML context, the activity of the enzyme aldo-keto reductase 1C3 (AKR1C3) is a crucial factor in chemotherapy resistance, as it mediates the intracellular transformation of anthracyclines to less active hydroxy metabolites. Here, we report that midostaurin is a potent inhibitor of Dau inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in a transfected cell model. Likewise, in the FLT3− AML cell line KG1a, midostaurin was able to increase the cellular accumulation of Dau and significantly decrease its metabolism by AKR1C3 simultaneously. The combination of those mechanisms increased the nuclear localization of Dau, thus synergizing its cytotoxic effects on KG1a cells. Our results provide new in vitro evidence of how the therapeutic activity of midostaurin could operate beyond targeting the FLT3 receptor.
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Abbreviations
- ABC:
-
ATP-binding cassette
- AKR:
-
Aldo-keto reductase
- AML:
-
Acute myeloid leukaemia
- CI:
-
Combination index
- CRE:
-
Carbonyl-reducing enzyme
- Dau:
-
Daunorubicin
- Dau-ol:
-
Daunorubicinol
- DMSO:
-
Dimethyl sulfoxide
- Fa:
-
Fraction affected
- FLT3:
-
FMS-like tyrosine kinase 3 receptor
- HCT116-AKR1C3:
-
Cells transfected with pCI_AKR1C3
- Mid:
-
Midostaurin
- MTT:
-
3-(4,5-Dimethylthiazolyl-2-yl)2,5-diphenyl tetrazolium bromide
- MDR:
-
Multidrug resistance
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- PGD2:
-
Prostaglandin D2
- 11β-PGF2α:
-
11β-Prostaglandin F2α
- PPARγ:
-
Peroxisome proliferator-activated receptor gamma
- SD:
-
Standard deviation
- SDR:
-
Short-chain dehydrogenase/reductase
- TKI:
-
Tyrosine kinase inhibitor
- UHPLC:
-
Ultra high-performance liquid chromatography
- WT:
-
Wild type
- 15dPGJ2:
-
15-DeoxyΔ12,14PGJ2
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Acknowledgements
This work was supported by Czech Science Foundation (project no. 16-26849S), by Grant Agency of Charles University (project no. 1006218) 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) and language editing was provided by Elsevier. Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the program “Projects of Large Research, Development, and Innovations Infrastructures”.
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Morell, A., Novotná, E., Milan, J. et al. Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism. Arch Toxicol 95, 67–78 (2021). https://doi.org/10.1007/s00204-020-02884-2
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DOI: https://doi.org/10.1007/s00204-020-02884-2