Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation.
Cancer Res
; 68(18): 7466-74, 2008 Sep 15.
Article
en En
| MEDLINE
| ID: mdl-18794134
In response to DNA damage, the ATM protein kinase activates signal transduction pathways essential for coordinating cell cycle progression with DNA repair. In the human disease ataxia-telangiectasia, mutation of the ATM gene results in multiple cellular defects, including enhanced sensitivity to ionizing radiation (IR). This phenotype highlights ATM as a potential target for novel inhibitors that could be used to enhance tumor cell sensitivity to radiotherapy. A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified. The compound is nontoxic and does not inhibit phosphatidylinositol 3-kinase (PI3K) or PI3K-like protein kinase family members in cells. CP466722 inhibited cellular ATM-dependent phosphorylation events and disruption of ATM function resulted in characteristic cell cycle checkpoint defects. Inhibition of cellular ATM kinase activity was rapidly and completely reversed by removing CP466722. Interestingly, clonogenic survival assays showed that transient inhibition of ATM is sufficient to sensitize cells to IR and suggests that therapeutic radiosensitization may only require ATM inhibition for short periods of time. The ability of CP466722 to rapidly and reversibly regulate ATM activity provides a new tool to ask questions about ATM function that could not easily be addressed using genetic models or RNA interference technologies.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tolerancia a Radiación
/
Daño del ADN
/
ADN de Neoplasias
/
Proteínas Serina-Treonina Quinasas
/
Proteínas de Ciclo Celular
/
Proteínas Supresoras de Tumor
/
Inhibidores de Proteínas Quinasas
/
Proteínas de Unión al ADN
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2008
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos