Mechanism of acridine-based telomerase inhibition and telomere shortening

Biochem Pharmacol. 2007 Sep 1;74(5):679-89. doi: 10.1016/j.bcp.2007.06.011. Epub 2007 Jun 16.

Abstract

The trisubstituted acridine compound BRACO-19 has been developed as a ligand for stabilising G-quadruplex structures. It is shown here that BRACO-19 produces short- and long-term growth arrest in cancer cell lines, and is significantly less potent in a normal cell line. BRACO-19 reduces telomerase activity and long-term telomere length attrition is observed. It is also shown that BRACO-19 binds to telomeric single-stranded overhang DNA, consistent with quadruplex formation, and the single-stranded protein hPOT1 has been shown to be displaced from the overhang in vitro and in cellular experiments. It is concluded that the cellular activity of BRACO-19 can be ascribed both to the uncapping of 3' telomere ends and to telomere shortening that may preferentially affect cells with short telomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemistry
  • Acridines / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Telomerase / antagonists & inhibitors*
  • Telomere / metabolism*

Substances

  • Acridines
  • Antineoplastic Agents
  • Telomerase
  • BRACO-19