Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth.
Eur J Cancer
; 48(16): 3093-103, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22366560
ABSTRACT
Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is strongly elevated compared to normal tissues and other malignancies. Most neuroblastoma cell lines lack this high BCL2 expression. Only two neuroblastoma cell lines (KCNR and SJNB12) show BCL2 expression levels representative for neuroblastoma tumours. To validate BCL2 as a therapeutic target in neuroblastoma we employed lentivirally mediated shRNA. Silencing of BCL2 in KCNR and SJNB12 resulted in massive apoptosis, while cell lines with low BCL2 expression were insensitive. Identical results were obtained by treatment of the neuroblastoma cell lines with the small molecule BCL2 inhibitor ABT263, which is currently being clinically evaluated. Combination assays of ABT263 with most classical cytostatics showed strong synergistic responses. Subcutaneous xenografts of a neuroblastoma cell line with high BCL2 expression in NMRI nu/nu mice showed a strong response to ABT263. These findings establish BCL2 as a promising drug target in neuroblastoma and warrant further evaluation of ABT263 and other BCL2 inhibiting drugs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
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Proteínas Proto-Oncogênicas c-bcl-2
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Terapia de Alvo Molecular
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Compostos de Anilina
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Neuroblastoma
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Cancer
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Holanda