The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration.
Int J Hematol
; 113(1): 100-105, 2021 Jan.
Article
en En
| MEDLINE
| ID: mdl-33025461
ABSTRACT
Nilotinib is a substrate of the breast cancer resistance protein (BCRP), which is a drug efflux transporter encoded by ABCG2 and regulates the pharmacokinetics of its substrates. We investigated the interaction between nilotinib and BCRP in chronic myeloid leukemia (CML) cells. An imatinib-resistant K562 cell line (K562/IM-R) treated with nilotinib was analyzed for BCRP expression, proliferation, apoptosis, and intracellular nilotinib concentration. K562/IM-R cells cultured with tyrosine kinase inhibitors (TKIs) showed an increased cell count and retained viability, whereas the growth of parental K562 cells was severely inhibited, suggesting that BCRP is involved in developing resistance to TKIs. Nilotinib-treated K562/IM-R cells showed a reduction in apoptosis; however, febuxostat pretreatment resulted in increased apoptosis. The intracellular concentration of nilotinib in K562/IM-R cells was significantly reduced compared to that in parental K562 cells, and febuxostat-pretreated K562/IM-R cells showed an increased intracellular nilotinib level compared to cells without pretreatment. The reduction in nilotinib levels caused by BCRP in CML cells might play a crucial role in resistance to TKIs. Moreover, febuxostat, as a BCRP inhibitor, could enhance nilotinib sensitivity, and combination therapy with nilotinib and febuxostat may represent a promising strategy for treatment of CML.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_leukemia
Asunto principal:
Pirimidinas
/
Expresión Génica
/
Febuxostat
/
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2
/
Proteínas de Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Int J Hematol
Asunto de la revista:
HEMATOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón