Redox Homeostasis and Beyond: The Role of Wild-Type Isocitrate Dehydrogenases for the Pathogenesis of Glioblastoma

Stegh, Alexander H.; Horbinski, Craig; Murnan, Kevin

doi:10.1089/ars.2023.0262

Cited by 3 publications

(2 citation statements)

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“…A profound inter-and intratumoral heterogeneity is a hallmark of GBM [36,37], which is thought to contribute to the differential response to treatment [38,39], and most likely accounts for the discrepancy in the response to CONA treatment observed in our study. Indeed, variation in the sensitivity to ROS-producing therapies has been linked to the heterogeneous level of antioxidant enzymes [40] or the status of the genes encoding isocitrate dehydrogenases (IDHs) 1 and 2 [41]. Furthermore, the IDH1 mutation or amplification of the gene encoding the epidermal growth factor receptor (EGFR) resulted in the overproduction of ROS, triggering severe oxidative stress [42,43] and modulated cell susceptibility to targeted therapies [41].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, variation in the sensitivity to ROS-producing therapies has been linked to the heterogeneous level of antioxidant enzymes [40] or the status of the genes encoding isocitrate dehydrogenases (IDHs) 1 and 2 [41]. Furthermore, the IDH1 mutation or amplification of the gene encoding the epidermal growth factor receptor (EGFR) resulted in the overproduction of ROS, triggering severe oxidative stress [42,43] and modulated cell susceptibility to targeted therapies [41].…”

Section: Discussionmentioning

confidence: 99%

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Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Szeliga

Rola

2023

Cells

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Compounds that cause oxidative stress have recently gained considerable interest as potential anticancer treatment modalities. Nevertheless, their efficiency may be diminished by the antioxidant systems often upregulated in cancer cells. Peroxiredoxins (PRDXs) are antioxidant enzymes that scavenge peroxides and contribute to redox homeostasis. They play a role in carcinogenesis and are upregulated in several cancer types. Here, we assessed the expression pattern of PRDX1 and PRDX2 in glioblastoma (GBM) and examined the efficacy of their inhibitors in GBM cell lines and patient-derived GBM cells. Both PRDX1 and PRDX2 were upregulated in GBM compared to non-tumor brain tissues and their considerable amounts were observed in GBM cells. Adenanthin, a compound inhibiting PRDX1 activity, slightly decreased GBM cell viability, while conoidin A (CONA), a covalent PRDX2 inhibitor, displayed high toxicity in GBM cells. CONA elevated the intracellular reactive oxygen species (ROS) level. Pre-treatment with an ROS scavenger protected cells from CONA-induced death, indicating that ROS accumulation plays a crucial role in this phenomenon. Menadione or celecoxib, both of which are ROS-inducing agents, potentiated the anticancer activity of CONA. Collectively, our results unveil PRDX1 and PRDX2 as potential targets for GBM therapy, and substantiate the further exploration of their inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Szeliga

Rola

2023

Cells

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The Cancer Antioxidant Regulation System in Therapeutic Resistance

Gu,

Mu,

Zheng

et al. 2024

Antioxidants

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Antioxidants play a pivotal role in neutralizing reactive oxygen species (ROS), which are known to induce oxidative stress. In the context of cancer development, cancer cells adeptly maintain elevated levels of both ROS and antioxidants through a process termed “redox reprogramming”. This balance optimizes the proliferative influence of ROS while simultaneously reducing the potential for ROS to cause damage to the cell. In some cases, the adapted antioxidant machinery can hamper the efficacy of treatments for neoplastic diseases, representing a significant facet of the resistance mechanisms observed in cancer therapy. In this review, we outline the contribution of antioxidant systems to therapeutic resistance. We detail the fundamental constituents of these systems, encompassing the central regulatory mechanisms involving transcription factors (of particular importance is the KEAP1/NRF2 signaling axis), the molecular effectors of antioxidants, and the auxiliary systems responsible for NADPH generation. Furthermore, we present recent clinical trials based on targeted antioxidant systems for the treatment of cancer, assessing the potential as well as challenges of this strategy in cancer therapy. Additionally, we summarize the pressing issues in the field, with the aim of illuminating a path toward the emergence of novel anticancer therapeutic approaches by orchestrating redox signaling.

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IDH2 Inhibitors Gain a Wildcard Status in the Cancer Therapeutics Competition

Piva,

Gharari,

Labrador

et al. 2024

Cancers

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The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies wild-type IDH2 as a crucial factor in the survival of triple-negative breast cancer (TNBC) cells, with its inhibition leading to disrupted energy metabolism, reduced tumor growth, and enhanced apoptosis. The second analysis examines the role of IDH2 in CD8+ T cells, revealing that its inhibition promotes the differentiation of memory T cells, thereby enhancing the efficacy of cell-based immunotherapies like CAR T cells. A third investigation supports these findings, demonstrating that IDH2 inhibition in CAR T cells reduces exhaustion, enhances memory T cell formation, and improves anti-tumor efficacy. Collectively, these reports highlight wild-type IDH2 as a promising therapeutic target, with potential applications as a two-edged sword in both cancer treatment and immunotherapy. The development of specific wild-type IDH2 inhibitors could offer new avenues for therapy, particularly in tumors reliant on IDH2 activity as well as in enhancing the effectiveness of CAR T cell therapies.

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Redox Homeostasis and Beyond: The Role of Wild-Type Isocitrate Dehydrogenases for the Pathogenesis of Glioblastoma

Cited by 3 publications

References 146 publications

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

The Cancer Antioxidant Regulation System in Therapeutic Resistance

IDH2 Inhibitors Gain a Wildcard Status in the Cancer Therapeutics Competition

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