title: 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.
authors.affiliation: Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, F-51096 Reims, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Brassart
authors.forename: Dennis
authors.initials: D
authors.lastname: Gomez
authors.forename: Anne
authors.initials: A
authors.lastname: De Cian
authors.forename: Rajaa
authors.initials: R
authors.lastname: Paterski
authors.forename: Alain
authors.initials: A
authors.lastname: Montagnac
authors.forename: Khuong-Huu
authors.initials: KH
authors.lastname: Qui
authors.forename: Nassima
authors.initials: N
authors.lastname: Temime-Smaali
authors.forename: Chantal
authors.initials: C
authors.lastname: Trentesaux
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.forename: Françoise
authors.initials: F
authors.lastname: Gueritte
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Riou
mesh_terms: D029062:Apocynaceae / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018515:Plant Leaves / Q000737:chemistry; D011278:Pregnanes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000737:chemistry* / Q000494:pharmacology; D000089804:Shelterin Complex; D013256:Steroids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D009841:Oligonucleotides; C440849:POT1 protein, human; D011278:Pregnanes; D011806:Quinolinium Compounds; D000089804:Shelterin Complex; D013256:Steroids; D034501:Telomere-Binding Proteins; C033097:malouetine; D004247:DNA; D019098:Telomerase