Overcoming hypoxia-induced apoptotic resistance through combinatorial inhibition of GSK-3ß and CDK1.
Cancer Res
; 71(15): 5265-75, 2011 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-21646472
ABSTRACT
Tumor hypoxia is an inherent impediment to cancer treatment that is both clinically significant and problematic. In this study, we conducted a cell-based screen to identify small molecules that could reverse the apoptotic resistance of hypoxic cancer cells. Among the compounds, we identified were a structurally related group that sensitized hypoxic cancer cells to apoptosis by inhibiting the kinases GSK-3ß and cyclin-dependent kinase (CDK) 1. Combinatorial inhibition of these proteins in hypoxic cancer cells and tumors increased levels of c-Myc and decreased expression of c-IAP2 and the central hypoxia response regulator hypoxia-inducible factor (HIF) 1α. In mice, these compounds augmented the hypoxic tumor cell death induced by cytotoxic chemotherapy, blocking angiogenesis and tumor growth. Taken together, our findings suggest that combinatorial inhibition of GSK-3ß and CDK1 augment the apoptotic sensitivity of hypoxic tumors, and they offer preclinical validation of a novel and readily translatable strategy to improve cancer therapy.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Tiazoles
/
Adenocarcinoma
/
Hipoxia de la Célula
/
Proteína Quinasa CDC2
/
Apoptosis
/
Neoplasias del Colon
/
Glucógeno Sintasa Quinasa 3
/
Inhibidores de Proteínas Quinasas
/
Subunidad alfa del Factor 1 Inducible por Hipoxia
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Res
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos