A novel approach to overcome multidrug resistance: utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors.
Eur J Pharm Sci
; 62: 274-80, 2014 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-24956463
ABSTRACT
We tried to overcome the paclitaxel (PTX) resistance of cancer cells due to P-glycoprotein (P-gp) overexpression in the in vivo anti-tumor chemotherapy by utilizing polyethylene glycol-modified liposomal paclitaxel (PL-PTX). First of all, established were PTX-resistant Colon-26 cancer cells (C26/PTX) overexpressing P-gp, which provided IC50 value of PTX solution about 30 times larger than that obtained for control C26 (C26/control) in the in vitro MTT assay. Western blot analysis confirmed P-gp expression in C26/PTX 10 times higher than that in C26/control, indicating that the resistance acquisition of C26/PTX to PTX would be ascribed to the enhanced efflux of PTX by P-gp overexpressed in C26/PTX. However, the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice was similar to that in C26/control-bearing mice. Double immunohistochemical staining of vascular endothelial cells and apoptotic cells within tumor tissues demonstrated that the apoptotic cell death was preferentially observed in vascular endothelial cells in C26/PTX tumors after intravenous administration of PL-PTX, while that was in tumor cells in C26/control tumors. These results suggest that the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice would be ascribed to the cytotoxic action of PTX pumped out of tumor cells by overexpressed P-gp to vascular endothelial cells in tumor tissues.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Paclitaxel
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Resistencia a Múltiples Medicamentos
/
Resistencia a Antineoplásicos
/
Neoplasias
/
Antineoplásicos Fitogénicos
Límite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Asunto de la revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Japón