Inhibition of efflux transporter ABCG2/BCRP does not restore mitoxantrone sensitivity in irinotecan-selected human leukemia CPT-K5 cells: evidence for multifactorial multidrug resistance.
Eur J Pharm Sci
; 29(2): 102-10, 2006 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-16844360
It has been shown that the human acute lymphoblastic leukemia (ALL) T cell line (RPMI 8402) selected with irinotecan (CPT-11) is transformed to a multidrug resistant (MDR) phenotype (CPT-K5) with cross-resistance to mitoxantrone (MX). Since MX is a well-documented substrate for the efflux transporter breast cancer resistant protein (BCRP/ABCG2), we assessed the contribution of drug efflux to MX resistance in CPT-K5 cells. Our results demonstrate that CPT-K5 cells had markedly higher expression levels of BCRP, negligible expression of MRP2 and P-gp, and lower intracellular retention of MX as compared to RPMI 8402 cells. Surprisingly, MX resistance in CPT-K5 cells was not reversed by the BCRP chemical inhibitor, novobiocin (NOV), or gene-specific siRNA, although intracellular MX concentrations were significantly increased when BCRP was functionally knocked down. These results suggest that up-regulation of BCRP plays a minimal role in conferring MX resistance to CPT-K5 cells, highlighting the existence of multiple, redundant mechanisms of drug resistance. The current results support the concept of "multifactorial multidrug resistance", a recently-described phenomenon that ascribes multidrug resistance to many possible cellular mechanisms, not only by efflux drug transporters.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Camptotecina
/
Mitoxantrona
/
Transportadores de Cassetes de Ligação de ATP
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Proteínas de Neoplasias
/
Antineoplásicos
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos