A new steroid derivative stabilizes g-quadruplexes and induces telomere uncapping in human tumor cells.

Abstract : 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.
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https://hal.archives-ouvertes.fr/hal-00184644
Contributor : Jocelyne Brunet <>
Submitted on : Wednesday, October 31, 2007 - 3:22:50 PM
Last modification on : Thursday, January 11, 2018 - 6:14:40 AM

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Alain Montagnac, Khuong-Huu Qui, Françoise Gueritte, B. Brassart, D. Gomez, et al.. A new steroid derivative stabilizes g-quadruplexes and induces telomere uncapping in human tumor cells.. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2007, 72 (3), pp.631-40. ⟨10.1124/mol.107.036574⟩. ⟨hal-00184644⟩

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