1. Academic Validation
  2. Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism

Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism

  • Arch Toxicol. 2021 Jan;95(1):67-78. doi: 10.1007/s00204-020-02884-2.
Anselm Morell 1 Eva Novotná 1 Jaroslav Milan 1 Petra Danielisová 1 Neslihan Büküm 1 Vladimír Wsól 2
Affiliations

Affiliations

  • 1 Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
  • 2 Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovského 1203, 50005, Hradec Králové, Czech Republic. wsol@faf.cuni.cz.
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.

Keywords

AKR1C3; AML therapy; Anthracyclines; Midostaurin; Multidrug resistance.

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