A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival.
Blood
; 105(11): 4484-91, 2005 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-15692065
ABSTRACT
B-cell chronic lymphocytic leukemia (B-CLL) is a clinically variable disease where mutations in DNA damage response genes ATM or TP53 affect the response to standard therapeutic agents. The in vitro cytotoxicity of a novel cyclin-dependent kinase inhibitor, CYC202, was evaluated in 26 B-CLLs, 11 with mutations in either the ATM or TP53 genes, and compared with that induced by ionizing radiation and fludarabine. CYC202 induced apoptosis within 24 hours of treatment in all 26 analyzed tumor samples independently of ATM and TP53 gene status, whereas 6 of 26 B-CLLs, mostly ATM mutant, showed marked in vitro resistance to fludarabine-induced apoptosis. Compared with B-CLLs, normal T and B lymphocytes treated with CYC202 displayed reduced and delayed apoptosis. Using global gene expression profiling, we found that CYC202 caused a significant down-regulation of genes involved in regulation of transcription, translation, survival, and DNA repair. Furthermore, induction of apoptosis by CYC202 was preceded by inhibition of RNA polymerase II phosphorylation, leading to down-regulation of several prosurvival proteins. We conclude that CYC202 is a potent inducer of apoptosis in B-CLL regardless of the functional status of the p53 pathway, and may be considered as a therapeutic agent to improve the outcome of resistant B-CLL tumors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Purinas
/
Transcrição Gênica
/
Leucemia Linfocítica Crônica de Células B
/
Regulação para Baixo
/
Apoptose
/
Quinases Ciclina-Dependentes
Limite:
Aged
/
Aged80
/
Humans
/
Middle aged
Idioma:
En
Revista:
Blood
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Reino Unido