Mechanism of acridine-based telomerase inhibition and telomere shortening

作者：Gunaratnam Mekala; Greciano Olga; Martins Cristina; Reszka Anthony P; Schultes Christoph M; Morjani Hamid; Riou Jean Francois; Neidle Stephen^*

来源：Biochemical Pharmacology, 2007, 74(5): 679-689.

DOI：10.1016/j.bcp.2007.06.011

• G-quadruplex ligands
• telomerase
• telomere targeting

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.

• 出版日期2007-9-1