A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells. Incles, C. M, Schultes, C. M, Kempski, H., Koehler, H., Kelland, L. R, & Neidle, S. Molecular cancer therapeutics, 3(10):1201–6, October, 2004.
Paper abstract bibtex The trisubstituted acridine derivative BRACO-19 has been designed to interact with and stabilize the quadruplex DNA structures that can be formed by folding of the single-stranded repeats at the 3' end of human telomeres. We suggest that the BRACO-19 complex inhibits the catalytic function of telomerase in human cancer cells and also destabilizes the telomerase-telomere capping complex so that cells enter senescence. Here, we present evidence showing that the inhibition of cell growth caused by BRACO-19 in DU145 prostate cancer cells occurs more rapidly than would be expected solely by the inhibition of the catalytic function of telomerase, and that senescence is accompanied by an initial up-regulation of the cyclin-dependent kinase inhibitor p21, with subsequent increases in p16(INK4a) expression. We also show that treatment with BRACO-19 causes extensive end-to-end chromosomal fusions, consistent with telomere uncapping.
@article{Incles2004,
title = {A {G}-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells.},
volume = {3},
issn = {1535-7163},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15486186},
abstract = {The trisubstituted acridine derivative BRACO-19 has been designed to interact with and stabilize the quadruplex DNA structures that can be formed by folding of the single-stranded repeats at the 3' end of human telomeres. We suggest that the BRACO-19 complex inhibits the catalytic function of telomerase in human cancer cells and also destabilizes the telomerase-telomere capping complex so that cells enter senescence. Here, we present evidence showing that the inhibition of cell growth caused by BRACO-19 in DU145 prostate cancer cells occurs more rapidly than would be expected solely by the inhibition of the catalytic function of telomerase, and that senescence is accompanied by an initial up-regulation of the cyclin-dependent kinase inhibitor p21, with subsequent increases in p16(INK4a) expression. We also show that treatment with BRACO-19 causes extensive end-to-end chromosomal fusions, consistent with telomere uncapping.},
number = {10},
journal = {Molecular cancer therapeutics},
author = {Incles, Christopher M and Schultes, Christoph M and Kempski, Helena and Koehler, Heike and Kelland, Lloyd R and Neidle, Stephen},
month = oct,
year = {2004},
pmid = {15486186},
keywords = {\#nosource, 3T3 Cells, Acridines, Acridines: pharmacology, Animals, Blotting, Catalysis, Cell Aging, Cell Line, Cell Proliferation, Chemical, Chromosomes, Chromosomes: ultrastructure, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p16: genetics, Cyclin-Dependent Kinase Inhibitor p16: metabolism, DNA, G-Quadruplexes, Humans, Ligands, Male, Metaphase, Mice, Models, Nucleic Acid Conformation, Prostatic Neoplasms, Prostatic Neoplasms: genetics, Prostatic Neoplasms: metabolism, Rhodamines, Rhodamines: pharmacology, Telomerase, Telomerase: metabolism, Telomere, Telomere: ultrastructure, Time Factors, Tumor, Up-Regulation, Western},
pages = {1201--6},
}
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