A G-quadruplex telomere targeting agent produces p16-associated senescence and chromosomal fusions in human prostate cancer cells

Mol Cancer Ther. 2004 Oct;3(10):1201-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Acridines / pharmacology
  • Animals
  • Blotting, Western
  • Catalysis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence*
  • Chromosomes / ultrastructure*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA*
  • G-Quadruplexes
  • Humans
  • Ligands
  • Male
  • Metaphase
  • Mice
  • Models, Chemical
  • Nucleic Acid Conformation
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Rhodamines / pharmacology
  • Telomerase / metabolism
  • Telomere / ultrastructure*
  • Time Factors
  • Up-Regulation

Substances

  • Acridines
  • Cyclin-Dependent Kinase Inhibitor p16
  • Ligands
  • Rhodamines
  • lissamine rhodamine B
  • DNA
  • Telomerase
  • BRACO-19