Dexamethasone Modulates Global DNA Methylation and Oxidative DNA Damage in Glioblastoma Cell Lines

Glioblastoma remains one of the most aggressive primary brain tumors, characterized by rapid progression, therapeutic resistance, and poor prognosis. Dexamethasone is routinely administered to patients with glioblastoma to reduce peritumoral edema and improve neurological symptoms. However, its broader molecular effects on tumor-cell biology and treatment response remain incompletely understood. This study examined the effects of dexamethasone alone and in combination with temozolomide, valproic acid, or metformin on glioblastoma cell viability, real-time proliferation, senescence-associated β-galactosidase activity, cell-cycle distribution, global DNA methylation, and oxidative DNA damage. Dexamethasone induced concentration- and time-dependent changes in global DNA methylation in glioma cells. In T98G cells, shorter exposure increased 5-methylcytosine, whereas longer incubation or selected combined treatment conditions reduced methylation, suggesting dynamic epigenetic remodeling. Low dexamethasone concentrations were associated with increased 5-methylcytosine content, also in temozolomide-containing conditions. In contrast, higher dexamethasone concentrations reduced global methylation. That effect was cell-line dependent. In SW1783 cells, high-dose dexamethasone caused a reduction in 5-methylcytosine amount as well as an increase in 8-oxo-2'-deoxyguanosine level. Dexamethasone also reduced real-time T98G cell proliferation after prolonged exposure, while temozolomide was the main compound associated with cell-cycle changes in T98G cells. Metformin displayed comparatively limited cytotoxicity under the tested conditions. Beyond dexamethasone's well-established anti-edematous and anti-inflammatory role, it may also modify glioma redox and epigenetic states and influence cellular responses to temozolomide, valproic acid, and metformin. When considering these findings it is necessary to take into account a number of limitations. The upper limits of the DEX, TMZ, and MF concentration ranges were one to three orders of magnitude higher than the brain or CSF exposure levels that have been reported, and the experiments were carried out at standard culture oxygen concentrations (about 18-21% O₂), which are much higher than the oxygen levels found in brain tissue (about 2-6% O₂). Furthermore, the conclusions drawn from the T98G experiments only apply to this cell line and cannot be applied to glioblastoma without first being verified in other models.