Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands.
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 IC50 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 beta-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.
Riou
J F
JF
Aventis Pharma SA, Centre de Recherche de Paris, 13 Quai Jules Guesde, BP 14, 94403 Vitry sur Seine, France.
Guittat
L
L
Mailliet
P
P
Laoui
A
A
Renou
E
E
Petitgenet
O
O
Mégnin-Chanet
F
F
Hélène
C
C
Mergny
J L
JL
D017209:Apoptosis; D002461:Cell Line, Transformed; D016922:Cellular Senescence; D004247:DNA; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000187:drug effects*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D008024:Ligands; D014227:Triazines; D004247:DNA; D019098:Telomerase