title: Telomere targeting with a new G4 ligand enhances radiation-induced killing of human glioblastoma cells.
abstract: 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 γH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 μmol/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.
authors: Laboratoire d’Immunologie, Clermont Université, Université d’Auvergne, Clermont-Ferrand, France.
authors: Patrick
authors: P
authors: Merle
authors: Bertrand
authors: B
authors: Evrard
authors: Anne
authors: A
authors: Petitjean
authors: Jean-Marie
authors: JM
authors: Lehn
authors: Marie-Paule
authors: MP
authors: Teulade-Fichou
authors: Emmanuel
authors: E
authors: Chautard
authors: Anne
authors: A
authors: De Cian
authors: Lionel
authors: L
authors: Guittat
authors: Phong Lan Thao
authors: PL
authors: Tran
authors: Jean-Louis
authors: JL
authors: Mergny
authors: Pierre
authors: P
authors: Verrelle
authors: Andreï
authors: A
authors: Tchirkov
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D048708:Cell Growth Processes / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004249:DNA Damage; D005260:Female; D054856:G-Quadruplexes; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008024:Ligands; D008698:Mesylates / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D008024:Ligands; D008698:Mesylates; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; C509186:TERT protein, human; D019098:Telomerase; C012077:trifluoromethanesulfonic acid