Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands
Open Access
- 19 February 2002
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 99 (5), 2672-2677
- https://doi.org/10.1073/pnas.052698099
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 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.Keywords
This publication has 49 references indexed in Scilit:
- Telomerase and cancer: time to move from a promising target to a clinical realityThe Journal of Pathology, 2001
- Expression of mutant telomerase in immortal telomerase-negative human cells results in cell cycle deregulation, nuclear and chromosomal abnormalities and rapid loss of viabilityOncogene, 2001
- Recent advances in the development of telomerase inhibitors for the treatment of cancerExpert Opinion on Investigational Drugs, 1999
- Energetics of strand-displacement reactions in triple helices: a spectroscopic studyJournal of Molecular Biology, 1999
- 2,7-Disubstituted Amidofluorenone Derivatives as Inhibitors of Human TelomeraseJournal of Medicinal Chemistry, 1999
- Extension of Life-Span by Introduction of Telomerase into Normal Human CellsScience, 1998
- Long G Tails at Both Ends of Human Chromosomes Suggest a C Strand Degradation Mechanism for Telomere ShorteningCell, 1997
- Heterogeneity in telomere length of human chromosomesHuman Molecular Genetics, 1996
- Specific Association of Human Telomerase Activity with Immortal Cells and CancerScience, 1994
- Effects of taxotere on murine and human tumor cell linesBiochemical and Biophysical Research Communications, 1992