TY - JOUR T1 - Biological Activity of the G-Quadruplex Ligand RHPS4 (3,11-Difluoro-6,8,13-trimethyl-8<em>H</em>-quino[4,3,2-<em>kl</em>]acridinium methosulfate) Is Associated with Telomere Capping Alteration JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1138 LP - 1146 DO - 10.1124/mol.104.001537 VL - 66 IS - 5 AU - Carlo Leonetti AU - Sarah Amodei AU - Carmen D'Angelo AU - Angela Rizzo AU - Barbara Benassi AU - Anna Antonelli AU - Raffaella Elli AU - Malcolm F. G. Stevens AU - Maurizio D'Incalci AU - Gabriella Zupi AU - Annamaria Biroccio Y1 - 2004/11/01 UR - http://molpharm.aspetjournals.org/content/66/5/1138.abstract N2 - This study had two goals: 1) to evaluate the biological effect of the novel pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to elucidate the relationship between G-quadruplex-based telomerase inhibitor-induced cellular effects and telomere length/dysfunction. The cellular pharmacological effects of RHPS4 have been evaluated by treating melanoma lines with increasing concentrations of RHPS4. A dose-dependent inhibition of cell proliferation was observed in all the lines during short-term treatment. Flow cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation of cells in the S-G2/M phase of cell cycle. The RHPS4-induced cell cycle alteration was irreversible even at low doses, and the cells died from apoptosis. At high RHPS4 concentration, apoptosis was accompanied by the induction of a senescence phenotype: large cell size, vacuolated cytoplasm, and β-galactosidase activity. The short-term biological activity of RHPS4 was not caused by telomere shortening, but it was associated with telomere dysfunction, in terms of presence of telomeric fusions, polynucleated cells, and typical images of telophase bridge. In conclusion, our results demonstrate that the G-quadruplex ligand RHPS4 can function in a telomere length-independent manner through its ability to cause telomere-capping alteration. ER -