Differential H 2 O 2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation

Amira Zaher; Kranti A Mapuskar; Jann N Sarkaria; Douglas R Spitz; Michael S Petronek; Bryan G Allen

doi:10.3390/ijms242417158

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Differential H 2 O 2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation

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Differential H 2 O 2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation

Amira Zaher, Kranti A Mapuskar, Jann N Sarkaria, Douglas R Spitz, Michael S Petronek and Bryan G Allen

International journal of molecular sciences, Vol.24(24), 17158

12/05/2023

DOI: 10.3390/ijms242417158

PMCID: PMC10743151

PMID: 38138986

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Abstract

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 H2O2 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.

glioblastoma

glioblastoma subtypes

DNA damage

hydrogen peroxide

pharmacological ascorbate

prooxidant

chemoradiation

antioxidant therapy

Details

Title: Subtitle: Differential H 2 O 2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation
Creators: Amira Zaher - University of Iowa
Kranti A Mapuskar - University of Iowa
Jann N Sarkaria - Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA
Douglas R Spitz - Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA
Michael S Petronek - University of Iowa
Bryan G Allen - University of Iowa
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.24(24), 17158
DOI: 10.3390/ijms242417158
PMID: 38138986
PMCID: PMC10743151
NLM abbreviation: Int J Mol Sci
eISSN: 1422-0067
Grant note: R21CA270742 / NCI NIH HHS P01CA244091 / NCI NIH HHS P01CA217797 / NCI NIH HHS P30CA086862 / NCI NIH HHS
Language: English
Date published: 12/05/2023
Academic Unit: Pathology; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984532057902771

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