Selective inhibition of aldo-keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism
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TOXICOKINETICS AND METABOLISM
Selective inhibition of aldo‑keto reductase 1C3: a novel mechanism involved in midostaurin and daunorubicin synergism Anselm Morell1 · Eva Novotná1 · Jaroslav Milan1 · Petra Danielisová1 · Neslihan Büküm1 · Vladimír Wsól1 Received: 26 May 2020 / Accepted: 13 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 F LT3− 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 · Anthracyclines · AML therapy · Midostaurin · Multidrug resistance 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)2,5diphenyl tetrazolium bromide Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02884-2) contains supplementary material, which is available to authorized users. * Vladimír Wsól [email protected] 1
Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
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
Introduction Recently, midostaurin (Rydapt, PKC412) became the first multitargeted tyrosine kinase inhibitor (TKI) to be approved by the US FDA and EMA for treating acute myeloid leukaemia (AML). This TKI r
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