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First published on June 22, 2007; DOI: 10.1124/mol.107.036574

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Received for publication March 29, 2007.
Revised June 15, 2007.
Accepted for publication June 20, 2007.

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

Bertrand Brassart 1, Dennis Gomez 1, Anne De Cian 2, Rajaa Paterski 1, Alain Montagnac 3, Khuong-Huu Qui 3, Nassima Temime-Smaali 1, Chantal Trentesaux 1, Jean-Louis Mergny 4, Francoise Gueritte 3, Jean-Francois Riou 5*

1 Je 2428 Onco-Pharmacologie 2 Museum National d'Histoire Naturelle 3 CNRS 4 Museum National d'histoire naturelle 5 JE 2428 Onco-Pharmacologie

* Address correspondence to: E-mail: jf.riou{at}univ-reims.fr

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 as 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 non-planar and non-aromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and 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


Key words: Resistance, DNA intercalation


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 Nucleic Acids ResHome page
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]


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