Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2.
Leuk Lymphoma
; 54(3): 569-78, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-22845311
ABSTRACT
Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr-Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC(50)) compared with parental K562 cells for imatinib (IC(50)(IM); 9 µM to 19 µM, p = 0.002) and nilotinib (IC(50)(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC(50)(IM) or IC(50)(NIL) or significantly decrease IC(50) upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Pirimidinas
/
Benzamidas
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Transportadoras de Casetes de Unión a ATP
/
Proteínas de Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Leuk Lymphoma
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2013
Tipo del documento:
Article
País de afiliación:
Australia