Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence.
Nucleic Acids Res
; 33(7): 2192-203, 2005.
Article
en En
| MEDLINE
| ID: mdl-15831792
ABSTRACT
The triazine derivative 12459 is a potent G-quadruplex interacting agent that inhibits telomerase activity. This agent induces time- and dose-dependent telomere shortening, senescence-like growth arrest and apoptosis in the human A549 tumour cell line. We show here that 12459 induces a delayed apoptosis that activates the mitochondrial pathway. A549 cell lines selected for resistance to 12459 and previously characterized for an altered hTERT expression also showed Bcl-2 overexpression. Transfection of Bcl-2 into A549 cells induced a resistance to the short-term apoptotic effect triggered by 12459, suggesting that Bcl-2 is an important determinant for the activity of 12459. In sharp contrast, the Bcl-2 overexpression was not sufficient to confer resistance to the senescence-like growth arrest induced by prolonged treatment with 12459. We also show that 12459 provokes a rapid degradation of the telomeric G-overhang in conditions that paralleled the apoptosis induction. In contrast, the G-overhang degradation was not observed when apoptosis was induced by camptothecin. Bcl-2 overexpression did not modify the G-overhang degradation, suggesting that this event is an early process uncoupled from the final apoptotic pathway.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Compuestos de Quinolinio
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Triazinas
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Apoptosis
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Proteínas Proto-Oncogénicas c-bcl-2
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Antineoplásicos
Tipo de estudio:
Risk_factors_studies
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2005
Tipo del documento:
Article