title: Mechanism of acridine-based telomerase inhibition and telomere shortening.
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.
authors.affiliation: CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.forename: Olga
authors.initials: O
authors.lastname: Greciano
authors.forename: Cristina
authors.initials: C
authors.lastname: Martins
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Reszka
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schultes
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Riou
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000378:metabolism*
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D019098:Telomerase; C454064:BRACO-19