Telomere targeting with a new G4 ligand enhances radiation-induced killing of human glioblastoma cells.
Fiche publication
Date publication
octobre 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Pr LEHN Jean-Marie
Tous les auteurs :
Merle P, Evrard B, Petitjean A, Lehn JM, Teulade-Fichou MP, Chautard E, De Cian A, Guittat L, Tran PL, Mergny JL, Verrelle P, Tchirkov A
Lien Pubmed
Résumé
The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and gammaH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 mumol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications.
Référence
Mol Cancer Ther. 2011 Oct;10(10):1784-95.