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

Kawashima, Kotaro; Ikemura, Kenji; Takemura, Miho; Toyozumi, Yuji; Okuda, Masahiro

doi:https://doi.org/10.1016/j.biopha.2024.117709

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

Kawashima, Kotaro; Ikemura, Kenji; Takemura, Miho et al.

Biomedicine and Pharmacotherapy, 2024, 181, 117709

アクセス数:410件（2025-07-26 11:39 集計）

固定URL: https://hdl.handle.net/11094/99698

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タイトル	Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells
著者	著者名 Kawashima, Kotaro
	NRID 1000070513935 1000070513935 ORCID 0000-0003-1870-9571 0000-0003-1870-9571 researchmap permalink Kenji_Ikemura Kenji_Ikemura Scopus Author ID 36783115100 36783115100 著者名 Ikemura, Kenji
	著者名 Takemura, Miho
	著者名 Toyozumi, Yuji
	NRID 1000070252426 1000070252426 researchmap permalink read0042639 read0042639 Scopus Author ID 56856467300 56856467300 著者名 Okuda, Masahiro
キーワード等	ATP-binding cassette subfamily G member 2
	Chronic myeloid leukemia
	Dasatinib
	Febuxostat
内容	Kawashima K., Ikemura K., Takemura M., et al. Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells. Biomedicine and Pharmacotherapy 181, 117709 (2024); https://doi.org/10.1016/j.biopha.2024.117709.
抄録	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.
出版者	Elsevier Masson s.r.l.
収録物名	Biomedicine and Pharmacotherapy
巻(号)	181
ページ	117709
刊行年月	2024-12-01
言語	英語
ハンドルURL	https://hdl.handle.net/11094/99698
PISSN	07533322
eISSN	19506007
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1016/j.biopha.2024.117709
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Biomedicine and Pharmacotherapy. 2024, 181, p. 117709
DC.title	Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells
DC.creator	Kawashima, Kotaro
	Ikemura, Kenji
	Takemura, Miho
	Toyozumi, Yuji
	Okuda, Masahiro
DC.publisher	Elsevier Masson s.r.l.
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-12-01
DC.identifier	https://doi.org/10.1016/j.biopha.2024.117709
DC.subject	ATP-binding cassette subfamily G member 2
	Chronic myeloid leukemia
	Dasatinib
	Febuxostat
DC.description	Kawashima K., Ikemura K., Takemura M., et al. Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells. Biomedicine and Pharmacotherapy 181, 117709 (2024); https://doi.org/10.1016/j.biopha.2024.117709.
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	99698
citation_title	Febuxostat enhances the efficacy of dasatinib by inhibiting ATP-binding cassette subfamily G member 2 (ABCG2) in chronic myeloid leukemia cells
citation_author	Kawashima, Kotaro
	Ikemura, Kenji
	Takemura, Miho
	Toyozumi, Yuji
	Okuda, Masahiro
citation_publisher	Elsevier Masson s.r.l.
citation_language	英語
citation_date	2024-12-01
citation_journal_title	Biomedicine and Pharmacotherapy
citation_volume	181
citation_firstpage	117709
citation_doi	https://doi.org/10.1016/j.biopha.2024.117709
citation_public_url	https://hdl.handle.net/11094/99698

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

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