Differential H 2 O 2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation.
Amira ZaherKranti A MapuskarJann N SarkariaDouglas R SpitzMichael S PetronekBryan G AllenPublished in: International journal of molecular sciences (2023)
Glioblastoma (GBM), a highly lethal and aggressive central nervous system malignancy, presents a critical need for targeted therapeutic approaches to improve patient outcomes in conjunction with standard-of-care (SOC) treatment. Molecular subtyping based on genetic profiles and metabolic characteristics has advanced our understanding of GBM to better predict its evolution, mechanisms, and treatment regimens. Pharmacological ascorbate (P-AscH - ) has emerged as a promising supplementary cancer therapy, leveraging its pro-oxidant properties to selectively kill malignant cells when combined with SOC. Given the clinical challenges posed by the heterogeneity and resistance of various GBM subtypes to conventional SOC, our study assessed the response of classical, mesenchymal, and proneural GBM to P-AscH - . P-AscH - (20 pmol/cell) combined with SOC (5 µM temozolomide and 4 Gy of radiation) enhanced clonogenic cell killing in classical and mesenchymal GBM subtypes, with limited effects in the proneural subtype. Similarly, following exposure to P-AscH - (20 pmol/cell), single-strand DNA damage significantly increased in classical and mesenchymal but not proneural GBM. Moreover, proneural GBM exhibited increased hydrogen peroxide removal rates, along with increased catalase and glutathione peroxidase activities compared to mesenchymal and classical GBM, demonstrating an altered H 2 O 2 metabolism that potentially drives differential P-AscH - toxicity. Taken together, these data suggest that P-AscH - may hold promise as an approach to improve SOC responsiveness in mesenchymal GBMs that are known for their resistance to SOC.
Keyphrases
- hydrogen peroxide
- bone marrow
- single cell
- stem cells
- cancer therapy
- dna damage
- cell therapy
- healthcare
- oxidative stress
- nitric oxide
- induced apoptosis
- palliative care
- machine learning
- big data
- rectal cancer
- dna repair
- electronic health record
- signaling pathway
- mesenchymal stem cells
- cell proliferation
- anti inflammatory
- artificial intelligence
- dna methylation
- pain management
- combination therapy
- single molecule
- newly diagnosed
- cell cycle arrest