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A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Laboratoire d'Onco-Pharmacologie, JE 2428, Unité de Formation et de Recherche de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France (B.B., D.G., R.P., N.T.-S., C.T., J.-F.R.); Institut National de la Santé et de la Recherche Médicale, U565, Acides Nucléiques: Dynamique, Ciblage et Fonctions Biologiques, Paris, France (A.D.C., J.-L.M.); Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 5153, Muséum National d'Histoire Naturelle USM503, Département de "Régulations, Développement et Diversité Moléculaire", Laboratoire des Régulations et Dynamique des Génomes, Paris, France (A.D.C., J.-L.M.); and Institut de Chimie des Substances Naturelles, Unité Propre de Recherche CNRS 2301, Gif sur Yvette, France (A.M., K.-H.Q., F.G.)

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.

Address correspondence to: Jean-François Riou, Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, F-51096 Reims, France. E-mail: jf.riou{at}univreims.fr

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				D. J. Patel, A. T. Phan, and V. Kuryavyi Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics Nucleic Acids Res., December 3, 2007; 35(22): 7429 - 7455. [Abstract] [Full Text] [PDF]