Potent Inhibition of Telomerase by Small-Molecule Pentacyclic Acridines Capable of Interacting with G-Quadruplexes

• DOI: 10.1124/mol.60.5.981
• Publication Date: 2018-01-08T20:43:54Z
• Authors: Sharon M. Gowan; Robert Heald; Malcolm F. G. Ste...; Lloyd R. Kelland
• Keywords: Growth inhibition; Acridine

A novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8<i>H</i>-quino[4,3,2-kl]acridinium methosulfate (RHPS4), has been identified as a potent inhibitor of telomerase in the cell-free telomeric repeat amplification protocol (TRAP). Modeling and biophysical studies suggest that RHPS4 inhibits through stabilization four-stranded G-quadruplex structures formed by single-stranded DNA. In contrast to interactive inhibitors described previously, inhibited at submicromolar levels (50% inhibition TRAP assay 0.33 ± 0.13 μM). Moreover, exhibited wide differential between this acute cellular cytotoxicity (mean IC₅₀ value 7.02 μM 4-day growth assay). RHPS4, when added 21NT breast cancer cells nonacute cytotoxic concentrations (200 nM) every 3 4 days, induced marked cessation cell after 15 days. Similar effects were observed using another line possessing relatively short telomeres, A431 human vulval carcinoma cells, but not ovarian (SKOV-3) long telomeres. was accompanied an increase G₂/M phase cycle, reduction activity, lower expression <i>hTERT</i> gene. These occurred absence detectable telomere length measured slot blotting. also GM847 maintain telomeres nontelomerase alternative mechanism for lengthening (ALT) represents promising small molecule is induces inhibitory tumor lines prolonged (2-week) exposure drug concentrations.