TY - JOUR T1 - A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 631 LP - 640 DO - 10.1124/mol.107.036574 VL - 72 IS - 3 AU - Bertrand Brassart AU - Dennis Gomez AU - Anne De Cian AU - Rajaa Paterski AU - Alain Montagnac AU - Khuong-Huu Qui AU - Nassima Temime-Smaali AU - Chantal Trentesaux AU - Jean-Louis Mergny AU - Françoise Gueritte AU - Jean-François Riou Y1 - 2007/09/01 UR - http://molpharm.aspetjournals.org/content/72/3/631.abstract N2 - Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3′ single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNA-binding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs. The American Society for Pharmacology and Experimental Therapeutics ER -