An evaluation cascade for G-quadruplex telomere targeting agents in human cancer cells.

The targeting of telomerase and telomere maintenance in human cancer cells can be achieved by small molecules that induce the 3'single-stranded ends of telomeric DNA to fold up into four-stranded quadruplex structures that inhibit the action of the telomerase enzyme complex. In this chapter, we describe a series of biochemical, biophysical, and cellular assays that are used to evaluate the activity of new compounds, and so assess whether they are suitable for examination in xenograft models of human cancer. These assays evaluate quadruplex stabilisation properties, short- and long-term cell viability, telomerase enzymatic activity, cellular senescence, and telomere length changes.

[1]  Jean-Louis Mergny,et al.  A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells , 2007, Molecular Pharmacology.

[2]  Stephen Neidle,et al.  Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6- and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation. , 2006, Journal of medicinal chemistry.

[3]  Stephen Neidle,et al.  Mechanism of acridine-based telomerase inhibition and telomere shortening. , 2007, Biochemical pharmacology.

[4]  Jean-Louis Mergny,et al.  Targeting telomeres and telomerase. , 2008, Biochimie.

[5]  Jean-Louis Mergny,et al.  Affinity and selectivity of G4 ligands measured by FRET. , 2005, Nucleic acids symposium series.

[6]  Hamid Morjani,et al.  Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells* , 2006, Journal of Biological Chemistry.

[7]  Barbara Benassi,et al.  Biological Activity of the G-Quadruplex Ligand RHPS4 (3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) Is Associated with Telomere Capping Alteration , 2004, Molecular Pharmacology.

[8]  M. Teulade‐Fichou,et al.  A hitchhiker's guide to G-quadruplex ligands. , 2008, Organic & biomolecular chemistry.

[9]  Julie E Reed,et al.  TRAP-LIG, a modified telomere repeat amplification protocol assay to quantitate telomerase inhibition by small molecules. , 2008, Analytical biochemistry.

[10]  Stephen Neidle,et al.  The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. , 2005, Cancer research.

[11]  Jia-Heng Tan,et al.  Design of selective G-quadruplex ligands as potential anticancer agents. , 2008, Mini reviews in medicinal chemistry.

[12]  T. Bryan,et al.  Physiological relevance of telomeric G‐quadruplex formation: a potential drug target , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  K. Shin‐ya,et al.  The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells. , 2006, Cancer research.

[14]  C. Autexier,et al.  The structure and function of telomerase reverse transcriptase. , 2006, Annual review of biochemistry.

[15]  S. Neidle,et al.  Inhibition of human telomerase by a G-quadruplex-interactive compound. , 1997, Journal of medicinal chemistry.

[16]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[17]  E. Gilson,et al.  G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors , 2008, Clinical Cancer Research.

[18]  B. Guyen,et al.  Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[19]  J. Mergny,et al.  Telomerase inhibitors based on quadruplex ligands selected by a fluorescence assay , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[21]  W. Hahn,et al.  Inhibition of telomerase limits the growth of human cancer cells , 1999, Nature Medicine.