Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation
Abstract
:1. Introduction
2. Results
2.1. Glioblastoma Subtypes Exhibit a Differential Response to P-AscH− with SOC
2.2. DNA Damage Responses following P-AscH− Treatments Are Subtype-Dependent
2.3. GBM Subtypes Exhibit Subtype-Dependent Differences in Hydrogen Peroxide Metabolism
2.4. Increased P-AscH− Dosing Further Improves Overall Survival in a Murine Xenograft Model of Mesenchymal GBM
3. Discussion
4. Materials and Methods
4.1. Cell Lines
4.2. Colony Formation Assay
4.3. P-AscH− Treatments
4.4. Neutral and Alkaline Comet Assays
4.5. Hydrogen Peroxide Removal Assay
4.6. Catalase Activity Assay
4.7. Glutathione Peroxidase Activity Assay
4.8. U87 Xenograft Murine Model
4.9. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Phase | Active Treatment (2 Weeks) | Adjuvant Phase (2 Weeks) | ||||
---|---|---|---|---|---|---|
Treatment | IR | TMZ | P-AscH− | IR | TMZ | P-AscH− |
Control | - | - | - | - | - | - |
SOC | 2 Gy × 3 weekly. | 2.5 mg kg−1 weekly | - | - | 2.5 mg kg−1 weekly | - |
Sequence 1 | 2 Gy × 3 weekly. | 2.5 mg kg−1 weekly | 4 g kg−1 × 3 weekly | - | 2.5 mg kg−1 weekly | 4 g kg−1 weekly |
Sequence 2 | 2 Gy × 3 weekly. | 2.5 mg kg−1 weekly | 4 g kg−1 × 5 weekly | - | 2.5 mg kg−1 weekly | 4 g kg−1 weekly |
Cell Line | Source | Subtype | Sex | IDH Status | MGMT Methylation |
---|---|---|---|---|---|
U251 | Millipore Sigma | Mesenchymal | M | Wild-type | Unmethylated |
U87 | ATCC | Mesenchymal | M | Wild-type | Unmethylated |
* GBM06 | Primary tumor | Classical | M | Wild-type | Unmethylated |
* GBM76 | Recurrent tumor | Classical | M | Wild-type | Methylated |
* GBM39 | Primary tumor | Mesenchymal | M | Wild-type | Methylated |
* GBM117 | Primary tumor | Proneural | M | Wild-type | Methylated |
* GBM85 | Primary tumor | Proneural | M | Wild-type | Methylated |
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Zaher, A.; Mapuskar, K.A.; Sarkaria, J.N.; Spitz, D.R.; Petronek, M.S.; Allen, B.G. Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation. Int. J. Mol. Sci. 2023, 24, 17158. https://doi.org/10.3390/ijms242417158
Zaher A, Mapuskar KA, Sarkaria JN, Spitz DR, Petronek MS, Allen BG. Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation. International Journal of Molecular Sciences. 2023; 24(24):17158. https://doi.org/10.3390/ijms242417158
Chicago/Turabian StyleZaher, Amira, Kranti A. Mapuskar, Jann N. Sarkaria, Douglas R. Spitz, Michael S. Petronek, and Bryan G. Allen. 2023. "Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation" International Journal of Molecular Sciences 24, no. 24: 17158. https://doi.org/10.3390/ijms242417158