PMID:17586599
| Citation |
Brassart, B, Gomez, D, De Cian, A, Paterski, R, Montagnac, A, Qui, KH, Temime-Smaali, N, Trentesaux, C, Mergny, JL, Gueritte, F and Riou, JF (2007) A new steroid derivative stabilizes g-quadruplexes and induces telomere uncapping in human tumor cells. Mol. Pharmacol. 72:631-40 |
|---|---|
| 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. |
| Links |
PubMed Online version:10.1124/mol.107.036574 |
| Keywords |
Apocynaceae/chemistry; Cell Line, Tumor; DNA/metabolism; DNA Damage; Dose-Response Relationship, Drug; Humans; Ligands; Molecular Structure; Oligonucleotides/chemical synthesis; Oligonucleotides/chemistry; Oligonucleotides/metabolism; Plant Leaves/chemistry; Pregnanes/chemistry; Pregnanes/isolation & purification; Pregnanes/metabolism; Pregnanes/pharmacology; Quinolinium Compounds/chemistry; Quinolinium Compounds/pharmacology; Steroids/chemistry; Steroids/isolation & purification; Steroids/metabolism; Steroids/pharmacology; Telomerase/antagonists & inhibitors; Telomere/chemistry; Telomere/metabolism; Telomere-Binding Proteins/genetics; Telomere-Binding Proteins/metabolism |
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