Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells?
Pharmacol Res
; 67(1): 79-83, 2013 Jan.
Article
en En
| MEDLINE
| ID: mdl-23103446
ABSTRACT
The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukaemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional analysis of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We observed that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Resistencia a Antineoplásicos
/
Inhibidores de Proteínas Quinasas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Año:
2013
Tipo del documento:
Article