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dc.contributor.authorGowan, SMen_US
dc.contributor.authorHeald, Ren_US
dc.contributor.authorStevens, MFGen_US
dc.contributor.authorKelland, LRen_US
dc.identifier.citationMOLECULAR PHARMACOLOGY, 2001, 60 pp. 981 - 988en_US
dc.description.abstractA novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8H-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 telomerase through stabilization of four-stranded G-quadruplex structures formed by single-stranded telomeric DNA. In contrast to G-quadruplex interactive telomerase inhibitors described previously, RHPS4 inhibited telomerase at submicromolar levels (50% inhibition in the TRAP assay at 0.33 +/- 0.13 muM). Moreover, RHPS4 exhibited a wide differential between this potent inhibition of telomerase and acute cellular cytotoxicity (mean IC50 value of 7.02 muM in 4-day growth inhibition assay). RHPS4, when added to 21 NT breast cancer cells at nonacute cytotoxic concentrations (200 nM) every 3 to 4 days, induced a marked cessation in cell growth after 15 days. Similar effects were observed using another cell line possessing relatively short telomeres,: A431 human vulval carcinoma cells, but not in a human ovarian carcinoma cell line (SKOV-3) possessing relatively long telomeres. In 21NT cells, growth cessation was accompanied by an increase in cells in the G(2)/M phase of the cell cycle,: a reduction in cellular telomerase activity, and a lower expression of the hTERT gene. These effects occurred in the absence of a detectable reduction in telomere length as measured by slot blotting. RHPS4 also induced a cessation of growth of GM847 cells that maintain telomeres by a nontelomerase alternative mechanism for lengthening telomeres (ALT) after 15 days. RHPS4 represents a promising G-quadruplex interactive small molecule that is a potent cell-free inhibitor of human telomerase and induces growth inhibitory effects in human tumor cell lines after prolonged (2-week) exposure to nonacute cytotoxic drug concentrations.en_US
dc.format.extent981 - 988en_US
dc.titlePotent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexesen_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
pubs.notesunique-id: ISI:000171985300013en_US
pubs.notesNot knownen_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorKelland, Lloyden_US

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