SOD2-mediated TMZ-resistant Glioblastoma Cells Exhibit Cross-resistance to Irradiation

Glioblastoma (GBM) is a highly aggressive brain tumor associated with poor prognosis and frequent resistance to standard treatments, including temozolomide (TMZ) and radiotherapy. Our previous study identified superoxide dismutase 2 (SOD2) as a key contributor to TMZ resistance through enhanced antioxidant defenses. This study aimed to determine whether SOD2 also plays a role in reduced radiation sensitivity in TMZ-resistant GBM cells. Clonogenic assays were used to assess the radiation response of TMZ-resistant U87MG and A172 cells. A pharmacological SOD inhibitor (SODi), sodium diethyldithiocarbamate trihydrate, was applied to evaluate its effect on radiosensitivity. An in vivo subcutaneous xenograft model derived from resistant U87MG cells was used to examine the efficacy of combination therapy with TMZ, irradiation, and SODi. Tumor progression was monitored using a bioluminescence imaging system. TMZ-resistant GBM cells demonstrated enhanced survival after 4 Gy radiation exposure, indicating a cross-resistance phenotype. SODi treatment significantly reduced colony formation in vitro and restored sensitivity to irradiation. In vivo, the triple combination of TMZ, irradiation, and SODi markedly suppressed tumor growth compared to other treatment groups. SOD2 contributes to both TMZ and radiation resistance in GBM. Targeting resistance-associated pathways may offer a promising strategy to improve the efficacy of radiochemotherapy in treatment-refractory glioblastoma.