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Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands

2002; National Academy of Sciences; Volume: 99; Issue: 5 Linguagem: Inglês

10.1073/pnas.052698099

1091-6490

Jean‐François Riou, Lionel Guittat, Patrick Mailliet, Abdelazize Laoui, E. Renou, Odile Petitgenet, Frédérique Mégnin-Chanet, C. Hélène, Jean‐Louis Mergny,

RNA Interference and Gene Delivery

Telomeres of human chromosomes contain a G-rich 3′-overhang that adopts an intramolecular G-quadruplex structure in vitro which blocks the catalytic reaction of telomerase. Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase and can therefore act as antitumor agents. We have identified by Fluorescence Resonance Energy Transfer a new series of quinoline-based G-quadruplex ligands that also exhibit potent and specific anti-telomerase activity with IC 50 in the nanomolar concentration range. Long term treatment of tumor cells at subapoptotic dosage induces a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of the senescent cell phenotype (large size and expression of β-galactosidase activity). Our data show that a G-quadruplex interacting agent is able to impair telomerase function in a tumor cell thus providing a basis for the development of new anticancer agents.