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.
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.
Douarre
Céline
C
Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne 51 rue Cognacq-Jay, 51096 Reims, France.
Gomez
Dennis
D
Morjani
Hamid
H
Zahm
Jean-Marie
JM
O'donohue
Marie-Françoise
MF
Eddabra
Lahcen
L
Mailliet
Patrick
P
Riou
Jean-François
JF
Trentesaux
Chantal
C
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D019008:Drug Resistance, Neoplasm; D006147:Guanine / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011806:Quinolinium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016615:Telomere / Q000737:chemistry / Q000187:drug effects; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; C480235:G-quadruplex ligand 12459; D019253:Proto-Oncogene Proteins c-bcl-2; D011806:Quinolinium Compounds; D014227:Triazines; D006147:Guanine