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SOD2-mediated TMZ-resistant Glioblastoma Cells Exhibit Cross-resistance to Irradiation
Wei-Ting Hsueh1, Kwang-Yu Chang1,2,3, Jian-Ying Chuang4
1Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
Background/Aim:
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.
Materials And Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Superoxide dismutase 2 (SOD2) contributes to glioblastoma resistance to both chemotherapy and radiation. Inhibiting SOD2 may improve treatment outcomes for refractory glioblastoma patients.
Area of Science:
- Oncology
- Cancer Research
- Molecular Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- Standard treatments like temozolomide (TMZ) and radiotherapy often face resistance.
- Previous work identified superoxide dismutase 2 (SOD2) as crucial for TMZ resistance.
Purpose of the Study:
- To investigate the role of SOD2 in radiation resistance in TMZ-resistant GBM cells.
- To determine if SOD2 inhibition can re-sensitize GBM cells to radiation therapy.
Main Methods:
- Utilized clonogenic assays to assess radiation response in TMZ-resistant GBM cell lines (U87MG, A172).
- Employed a pharmacological SOD inhibitor (SODi) to evaluate its impact on radiosensitivity.
- Established an *in vivo* subcutaneous xenograft model using resistant U87MG cells to test combination therapy (TMZ, irradiation, SODi).
- Monitored tumor progression via bioluminescence imaging.
Main Results:
- TMZ-resistant GBM cells exhibited cross-resistance to radiation (4 Gy).
- SODi treatment significantly reduced *in vitro* colony formation and restored radiation sensitivity.
- *In vivo* studies showed the triple combination therapy (TMZ, irradiation, SODi) markedly suppressed tumor growth.
Conclusions:
- SOD2 plays a significant role in both temozolomide and radiation resistance in glioblastoma.
- Targeting SOD2-mediated resistance pathways presents a potential strategy to enhance radiochemotherapy efficacy in treatment-refractory GBM.
