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PMID: 11854467 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 5 ·2002-03-05 ·Pages 2672-7

Riou JF, Guittat L, Mailliet P, Laoui A, Renou E, Petitgenet O, Mégnin-Chanet F, Hélène C, Mergny JL

Abstract

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.

MeSH Terms
Apoptosis Cell Line, Transformed Cellular Senescence DNA G-Quadruplexes Humans Ligands Molecular Structure Telomerase/metabolism Telomere/drug effects Triazines/chemistry,pharmacology Tumor Cells, Cultured
Chemicals
Ligands Triazines DNA Telomerase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Riou J F
Aventis Pharma SA, Centre de Recherche de Paris, 13 Quai Jules Guesde, BP 14, 94403 Vitry sur Seine, France.
Guittat L
Mailliet P
Laoui A
Renou E
Petitgenet O
Mégnin-Chanet F
Hélène C
Mergny J L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.052698099
Published
2002-03-05
Epub
2002-00-19
Pages
2672-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC122406
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.052698099 PMC Full Text View journal details
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