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Nucleic Acids Research 2005 33(7):2192-2203; doi:10.1093/nar/gki514
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Published online 14 April 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

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

Céline Douarre1, Dennis Gomez1,2, Hamid Morjani1, Jean-Marie Zahm3, Marie-Françoise O'Donohue4, Lahcen Eddabra1, Patrick Mailliet5, Jean-François Riou1,* and Chantal Trentesaux1

1Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne 51 rue Cognacq-Jay, 51096 Reims, France 2Laboratoire de Biophysique, Muséum National d'Histoire Naturelle, USM503, INSERM U565, CNRS UMR 5153 43 rue Cuvier, 75231 Paris cedex 05, France 3INSERM UMR 514, CHU Maison Blanche 45 rue Cognacq-Jay, 51092 Reims, France 4CNRS UMR 6142, UFR de Pharmacie, Université de Reims Champagne-Ardenne 51 rue Cognacq-Jay, 51096, Reims, France 5Sanofi-Aventis SA, Département de Chimie, Centre de Recherche de Paris 13 quai Jules Guesde, 94403 Vitry sur Seine, France

*To whom correspondence should be addressed. Tel: +33 3 26 91 80 13; Fax: +33 3 26 91 89 26; Email: jf.riou{at}univ-reims.fr

Received February 11, 2005. Revised March 29, 2005. Accepted March 29, 2005.

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.


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