Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells.

Autor: Kawashima K; Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 5650871, Japan., Ikemura K; Department of Pharmacy, Osaka University Hospital, Suita, Osaka 5650871, Japan; Department of Hospital Pharmacy, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan. Electronic address: ikemurak@hp-drug.med.osaka-u.ac.jp., Takemura M; Department of Clinical Pharmacy Research and Education, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 5650871, Japan., Toyozumi Y; Department of Hospital Pharmacy, School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 5650871, Japan., Okuda M; Department of Pharmacy, Osaka University Hospital, Suita, Osaka 5650871, Japan; Department of Hospital Pharmacy, Graduate School of Medicine, Osaka University, Suita, Osaka 5650871, Japan.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Dec; Vol. 181, pp. 117709. Date of Electronic Publication: 2024 Nov 25.
DOI: 10.1016/j.biopha.2024.117709
Abstrakt: Dasatinib is a second-generation breakpoint cluster region-abelson 1 (BCR::ABL1) tyrosine kinase inhibitor (TKI) used for the treatment of chronic myeloid leukemia (CML). Overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) in CML cells contributes to dasatinib resistance and poor chemotherapeutic responses. Considering that the xanthine oxidase inhibitor febuxostat has anti-ABCG2 activity, febuxostat may enhance the efficacy of dasatinib. However, the mechanism of action of febuxostat and its effects on the efficacy and safety of dasatinib in patients with CML are unknown. Therefore, this study aimed to retrospectively investigate the clinical impact of concomitant febuxostat on the efficacy of dasatinib in 65 patients with CML. Moreover, its underlying mechanism was explored in vitro using an ABCG2-overexpressing CML cell line (K562-ABCG2 cells). The retrospective study revealed that the achievement ratios of early molecular response at three months and major molecular response at 12 months after dasatinib treatment in patients with febuxostat were significantly higher than those in patients without febuxostat (91 % vs. 70 %, p = 0.034, 86 % vs. 53 %, p = 0.013, respectively). In vitro studies showed that febuxostat significantly decreased cell viability and increased the residual dasatinib concentration in dasatinib-treated K562-ABCG2 cells. Moreover, phosphorylated BCR::ABL1 levels in dasatinib-treated K562-ABCG2 cells were significantly decreased by febuxostat. Overall, concomitant febuxostat enhanced the efficacy of dasatinib in patients with CML. This was achieved partially by inhibition of ABCG2-mediated excretion of dasatinib from CML cells. Therefore, these findings provide important insights for improving CML treatment and overcoming TKI resistance.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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