A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells.
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.
Incles
Christopher M
CM
Cancer Research UK Biomolecular Structure Group, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Schultes
Christoph M
CM
Kempski
Helena
H
Koehler
Heike
H
Kelland
Lloyd R
LR
Neidle
Stephen
S
D016475:3T3 Cells; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D002875:Chromosomes / Q000648:ultrastructure*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004247:DNA; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D008297:Male; D008677:Metaphase; D051379:Mice; D008956:Models, Chemical; D009690:Nucleic Acid Conformation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012235:Rhodamines / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*; D013997:Time Factors; D015854:Up-Regulation
D000166:Acridines; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008024:Ligands; D012235:Rhodamines; C022027:lissamine rhodamine B; D004247:DNA; D019098:Telomerase; C454064:BRACO-19