Thioredoxin and Glutathione Systems in Glioblastoma: Mechanisms, Challenges and Targeting Opportunities

Dear Colleagues,

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Abnormal proliferation and metabolism increase reactive oxygen species (ROS), a hallmark of cancer cells including GBM. GBM cancer cells rely on the endogenous antioxidants, thioredoxin (Trx) and glutathione (GSH) systems to decrease ROS below the lethal threshold for their survival, tumor initiation and progression. Pro-oxidant anti-cancer strategies, including radiation therapy and redox chemotherapeutics, raise the intrinsically high ROS levels in cancer cells to a lethal threshold. However, Trx/GSH systems mediate adaptive ROS scavenging mechanisms, leading to chemoradiation resistance and tumor recurrence. Hence, Trx/GSH inhibition should be implemented to bypass Trx/GSH compensatory mechanisms.

In this Special Issue, we welcome original research articles and reviews aiming to advance our understanding of the function, regulation, targeting of Trx/GSH systems and combined strategies to improve the dismal outcome of patients with GBM.

We look forward to receiving your contributions.

Original research articles and reviews may include, but are not limited to, the following research topics investigated in GBM pre-clinical (in vitro or in vivo), clinical or computational studies:

(1) Expression, activity or regulation of enzymatic and non-enzymatic Trx and GSH antioxidant defense systems in GBM.

(2) Role of Trx and GSH systems in GBM redox homeostasis, redox signaling, tumor initiation, progression, metabolic alterations, resistance to treatment or tumor recurrence. This might include antioxidant activities regulating the levels of free radicals derived from oxygen (ROS) or nitrogen (reactive nitrogen species (RNS)).

(3) Cross-talk of Trx and GSH systems with each other as a backup compensatory mechanism, or with other antioxidant enzymes (such as, catalase, superoxide dismutase, peroxiredoxins), redox-sensitive tumor suppressor genes (such as TP53, PTEN), oncogenic receptor tyrosine kinases (EGFR, EGFRvIII) or any other signaling molecule.

(4) Conventional and innovative pre-clinical or clinical pro-oxidant strategies using an inhibitor of Trx and/or GSH system alone or in combination with treatment that directly or indirectly increases ROS or any other anti-cancer strategy, such as radiation therapy, chemotherapy, targeted therapies, redox mitochondria/metabolic targeting, redox mimetics, hypoxia-selective redox drugs, tumor-treating fields (TTF), metal-based nanocarriers, redox-active repurposed drugs (such as the pan-thioredoxin reductase inhibitor auranofin), natural products or synthetic derivatives, such as:

- Analysis of each treatment effect and/or combined treatment interactions to evaluate synergistic cellular (viability, proliferation, cell death, mitochondrial control of cell death), molecular effects/signaling pathways underlying response to Trx/GSH inhibitors and/or combined treatment;

- Mechanisms of resistance to Trx/GSH inhibitors in GBM: redox resetting to decrease oxidative stress and bypass the ROS lethal threshold in response to pro-oxidant Trx/GSH inhibitors, mechanisms regulating increased expression/activity of Trx/GSH antioxidants as ROS scavenging adaptive mechanisms, cross-talk with DNA damage, DNA repair mechanisms, abnormal metabolism or resistance to cell death mechanisms;

- Identification of a component of Trx and/or GSH system as a therapeutic vulnerability in GBM treatment, a chemo- or radiosensitizing target, or in synthetic lethal strategies;

- ROS scavenging compounds to evaluate the extent of ROS-mediated effects;

- GSH-depleting compounds to evaluate synergistic effects with inhibitors of the Trx system;

- Differential redox status between normal cells and GBM cancer cells, selectivity of Trx/GSH inhibitors and combined treatment to increase ROS to a cytotoxic threshold level in GBM cancer cells without affecting normal cells.

(5)  Redox biology of GBM stem cells (GSCs) such as the expression, activity and/or regulation of Trx/GSH systems in GSCs, the role of GSCs in response to Trx/GSH inhibitors and/or combined treatment, or resistance to chemoradiation standard treatment.

(6) Expression, activity and/or regulation of Trx/GSH systems in the tumor microenvironmemt (TME) such as, brain endothelial cells, neurons, astrocytes, oligodendrocytes, resident immune cells (microglia), tumor-infiltrating immune cells and their cross-talk with GBM tumor cells.

(7) Ability of Trx/GSH inhibitors to cross the blood–brain barrier (BBB) and strategies to overcome the limitations to cross the BBB.

(8) Oxidative stress biomarkers (lipid peroxidation, protein oxidation, DNA damage oxidation), biomarkers in response to Trx or GSH inhibitors in GBM pre-clinical in vivo models, in patient tissues, liquid biopsy clinical samples or datasets from publicly available databases of patients diagnosed with GBM.

Dr. Siham Sabri
Prof. Dr. Bassam S. Abdulkarim
Guest Editors

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• glioblastoma
• reactive oxygen species (ROS)
• thioredoxin/glutathione antioxidant systems
• thioredoxin/glutathione inhibitors
• pro-oxidant cancer therapeutics
• radiation therapy
• targeted therapies
• drug repurposing
• natural products
• combination therapy