The G-quadruplex-stabilising agent RHPS4 induces telomeric dysfunction and enhances radiosensitivity in glioblastoma cells

摘要: Abstract G-quadruplex (G4) interacting agents are a class of ligands that can bind to and stabilise secondary structures located in genomic G-rich regions such as telomeres. Stabilisation G4 leads telomere architecture disruption with consequent detrimental effect on cell proliferation, which makes these good candidates for chemotherapeutic purposes. RHPS4 is one the most effective well-studied very high specificity telomeric G4. In this work, we tested vitro efficacy astrocytoma lines, evaluated whether act radiosensitising agent by destabilising first part study, response was investigated four human lines (U251MG, U87MG, T67 T70) two normal primary fibroblast strains (AG01522 MRC5). Cell growth reduction, histone H2AX phosphorylation telomere-induced dysfunctional foci (TIF) formation were markedly higher cells than fibroblasts, despite absence shortening. second combined submicromolar concentrations X-rays assessed U251MG glioblastoma radioresistant line. Long-term curves, cycle analysis survival experiments, clearly showed synergistic treatment. Interestingly greater bearing number DNA double-strand breaks rejoining after irradiation revealed delayed repair kinetics pre-treated drug increase chromosome-type exchanges fusions. These findings provide evidence exposure radiosensitizes cells, suggesting potential future therapeutic applications.