Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity.
Cell Death Differ
; 10(5): 592-8, 2003 May.
Article
en En
| MEDLINE
| ID: mdl-12728257
Bcr-Abl is one of the most potent antiapoptotic molecules and is the tyrosine-kinase implicated in Philadelphia (Ph) chromosome-positive leukemia. It is still obscure how Bcr-Abl provides the leukemic cell a strong resistance to chemotherapeutic drugs. A rational drug development produced a specific inhibitor of the catalytic activity of Bcr-Abl called STI571. This drug was shown to eliminate Bcr-Abl-positive cells both in vitro and in vivo, although resistant cells may appear in culture and relapse occurs in some patients. In the study described here, Bcr-Abl-positive cells treated with tyrosine-kinase inhibitors such as herbimycin A, genistein or STI571 lost their phosphotyrosine-containing proteins, but were still extremely resistant to apoptosis. Therefore, in the absence of tyrosine-kinase activity, Bcr-Abl-positive cells continue to signal biochemically to prevent apoptosis induced by chemotherapeutic drugs. We propose that secondary antiapoptotic signals are entirely responsible for the resistance of Bcr-Abl-positive cells. Precise determination of such signals and rational drug development against them should improve the means to combat Ph chromosome-positive leukemia.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Pirimidinas
/
Proteínas Tirosina Quinasas
/
Proteínas de Fusión bcr-abl
/
Apoptosis
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Cell Death Differ
Año:
2003
Tipo del documento:
Article
País de afiliación:
Brasil
Pais de publicación:
Reino Unido