3-amino thioacridone inhibits DNA synthesis and induce DNA damage in T-cell acute lymphoblastic leukemia (T-ALL) in a p16-dependent manner.
J Exp Ther Oncol
; 4(3): 223-37, 2004 Oct.
Article
en En
| MEDLINE
| ID: mdl-15724842
ABSTRACT
In T-cell Acute Lymphocytic Leukemia (T-ALL), the inhibitors of cyclin-dependent kinases (CDK) 4 and 6, p16 and p15, are inactivated almost universally at the DNA, RNA and protein levels. This suggests that CDK-targeting may be an effective therapeutic approach for T-ALL and other cancers. In this study, we tested 3 inhibitors of CDK4, 3-aminothioacridone (3-ATA), thioacridone (TA), and oxindole, for their effects on DNA synthesis and viability in primary T-ALL. Each compound was an effective inhibitor, with overall IC(50)s in similar ranges. In colony formation assay, leukemic cells were approximately 10-fold more sensitive to 3-ATA than normal bone marrow cells. When sorted by G1 protein status of T-ALL, p16(+), p15(+) or pRb(-) samples were significantly less sensitive to 3-ATA and TA, but not to oxindole, than p16(-), p15(-) or pRb(+) samples. There was no relationship of sensitivity with ARF expression. Despite their in vitro function as inhibitors of CDK4, 3-ATA did not inhibit pRb phosphorylation or cause G1 arrest, but did cause DNA damage and result in the induction and phosphorylation of p53. We conclude that 3-ATA efficacy can be predicted by p16 status in T-ALL, but the mechanism of action may be distinct from their in vitro ability to regulate CDK4 kinase activity
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Banco de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
ADN
/
Leucemia-Linfoma de Células T del Adulto
/
Proteínas Proto-Oncogénicas
/
Quinasas Ciclina-Dependientes
/
Genes p16
/
Aminoacridinas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2004
Tipo del documento:
Article