Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1.
Pharmacogenomics J
; 5(2): 112-25, 2005.
Article
en En
| MEDLINE
| ID: mdl-15668728
To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Genes MDR
/
Elipticinas
/
Antineoplásicos Fitogénicos
Límite:
Humans
Idioma:
En
Revista:
Pharmacogenomics J
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACOLOGIA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos