Potential targets and treatments affect oxidative stress in gliomas: An overview of molecular mechanisms

Abstract

Oxidative stress refers to the imbalance between oxidation and antioxidant activity in the body. Oxygen is reduced by electrons as part of normal metabolism leading to the formation of various reactive oxygen species (ROS). ROS are the main cause of oxidative stress and can be assessed through direct detection. Oxidative stress is a double-edged phenomenon in that it has protective mechanisms that help to destroy bacteria and pathogens, however, increased ROS accumulation can lead to host cell apoptosis and damage. Glioma is one of the most common malignant tumors of the central nervous system and is characterized by changes in the redox state. Therapeutic regimens still encounter multiple obstacles and challenges. Glioma occurrence is related to increased free radical levels and decreased antioxidant defense responses. Oxidative stress is particularly important in the pathogenesis of gliomas, indicating that antioxidant therapy may be a means of treating tumors. This review evaluates oxidative stress and its effects on gliomas, describes the potential targets and therapeutic drugs in detail, and clarifies the effects of radiotherapy and chemotherapy on oxidative stress. These data may provide a reference for the development of precise therapeutic regimes of gliomas based on oxidative stress.

Introduction

Gliomas are common and arise from neuroglial progenitor cells. They are currently incurable central nervous system (CNS) tumors in adults, representing almost 80% of all malignant brain tumors (Ostrom et al., 2014). Glioma incidence and survival rate are associated with numerous factors. Brain tumor development is related to oxidative stress, therefore, it is important to understand oxidative stress mechanisms and develop novel and effective treatments.

In 1990, Sohal et al. first proposed the concept of oxidative stress, either caused by an increase in free radical production or a reduction in the scavenging capacity of the body, leading to disorders in the oxidation and antioxidant systems, resulting in oxidative damage by free radical accumulation (Sohal and Allen, 1990). This process is associated with electron transfer, which affects the redox state of the organism.

The species to which oxygen converts with high reactivity are generally called reactive oxygen species (ROS), which are a type of single electron reduction product of oxygen in vivo (Nosaka and Nosaka, 2017). ROS are toxic but are also necessary for regulating the diverse physiological functions of living organisms.

Antioxidative therapy is an effective strategy for many diseases triggered by excess ROS. Low and well-regulated ROS levels enable the functioning of a diverse array of signaling pathways. High levels of ROS-damaged proteins, lipids, and deoxyribonucleic acid (DNA) promote clonal expansion and tumor growth by protecting initial cells from oxidative toxicity and apoptosis (Reczek and Chandel, 2017). Therefore, antioxidative therapy could be used as a research target for glioma treatment. This review describes the existing evidence for the involvement of oxidative stress in the incidence of gliomas, focuses on understanding the function of ROS, and details how to manipulate ROS in glioma treatment.

Oxidative stress overview

Any atom or molecule containing one or more unpaired electrons is defined as a free radical. ROS is a collective concept consisting of oxygen-based free radicals and some non-radical derivatives of O₂, including hydrogen peroxide (H₂O₂), superoxide anion radicals (^•O₂⁻), hydroxyl radicals (•OH), and singlet oxygen (¹O₂) (Nosaka and Nosaka, 2017). The regulation of ROS production is shown in Figure 1. ROS have beneficial biological activities and are maintained at appropriate levels by endogenous antioxidant defenses, comprising non-enzymatic antioxidants and antioxidant enzymes. Non-enzymatic antioxidants include tocopherols, ascorbic acid, and glutathione (GSH). Generally, oxidative stress levels are measured using GSH. The antioxidant enzymes include catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase. Some endogenous pathways can generate ROS, such as the reduction of oxygen molecules during aerobic respiration, resulting in hydroxyl radicals and superoxide. Similarly, the oxidation of catecholamines and the activation of electrons in arachidonic acid co-products reduces oxygen molecules to superoxide (Betteridge, 2000). Many factors stimulate ROS production in various cell types, including cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), interferon-γ (IFN-γ), G protein-coupled receptor binding ligands angiotensin II, serotonin (5-hydroxytryptamine), bradykinin, thrombin, endothelin, and ion channel-linked receptors with neurotransmitters (e.g., acetylcholine, glutamate, glycine, and γ-aminobutyric acid) (Thannickal and Fanburg, 2000). Stimulated by growth factors, ROS act as secondary messenger molecules and initiate a signal cascade in receptor transduction, acting downstream of small guanosine triphosphate (GTP)-binding proteins and receptor tyrosine kinases (RTKs) and upstream of the mitogen-activated protein kinase (MAPK) family (Behrend et al., 2003). The MAPK family mainly consists of c-Jun N-terminal kinases (JNKs: JNK1, JNK2, and JNK3), extracellular signal-regulated kinases (ERKs: ERK1 and ERK2), and p38-MAPKs (p38-MAPKα, p38-MAPKβ, p38-MAPKγ, and p38-MAPKδ) (Wada and Penninger, 2004). JNKs are activated by the phosphorylation of threonine and tyrosine residues catalyzed by MAPK kinase 4 (MKK4) and MKK7, which in turn activate ETS-like protein 1, transcription factor 2, p53, and c-Myc to promote cancer cell proliferation (Wada and Penninger, 2004). Activator protein 1 (AP-1), which is composed of c-Jun and c-Fos, is a downstream transcription factor that is activated by MAPK. It also regulates cyclin D1 and p21 to promote cell proliferation (Waris and Ahsan, 2006). ROS can also be produced through a series of exogenous processes. Exposure to exogenous substances can induce oxidative stress and damage. In the case of ionizing radiation, water decomposes to produce hydroxyl radicals. A study has suggested that the majority of the subversive effects of O₂ are due to the action of oxygen radicals and an increase in the partial pressure of oxygen or reduction in antioxidant defenses can cause cellular and tissue damage. ^•O₂⁻, a free radical, is produced by the monovalent reduction of O₂ (Gerschman et al., 1954). From a biological perspective, ^•O₂⁻ can be generated from two major sources: phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the mitochondrial respiratory chain. Duve and Baudhuin described the process whereby peroxisomes can oxidize the substrate RH2, reducing oxygen to hydrogen peroxide. A large quantity of CAT can reduce hydrogen peroxide to water (O₂ + RH₂→R₂ + H₂O₂; H₂O₂ + RH₂→2H₂O + O₂ + R) (De Duve and Baudhuin, 1966). Peroxisomes not only participate in ROS generation but also scavenge ROS. Previous studies have shown that NADPH oxidase (NOX) is the principal source of ROS (Brown and Griendling, 2009). NOX is mainly composed of five subunits, including gp91phox (or its homologs, NOX1 and NOX4), p22phox, p47phox, p40phox, and p67phox and two GTP-binding proteins Rap1A and Rac2 (Burtenshaw et al., 2019).

FIGURE 1

The first SOD that catalyzes the dismutation of superoxide radicals and defends against oxygen free radicals was reported in 1969 (McCord and Fridovich, 1969). Studies have shown that SOD advances the reaction between itself and superoxide anions to form H₂O₂ and O₂ (^•O₂⁻ + ^•O₂⁻ + 2H⁺→O₂ + H₂O₂) (Fridovich, 1997). H₂O₂ reacts with iron ions to generate •OH in Fenton systems, inducing the production of 5,6-dihydroxycytosine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 8-hydroxyguanine (8-OHdG) and 4,6-diamino-5-formamidopyrimidine (Halliwell and Gutteridge, 1992). The content of these products can be measured as an index of DNA damage caused by •OH. CAT and peroxidase are inactivated by ^•O₂⁻, and SOD reduces the H₂O₂ burden borne by aerobic cells by maintaining the activities of peroxidases and CAT (Flint et al., 1993). In any environment where oxygen is produced, the activities of CAT and peroxidase are compromised, and SOD minimizes this effect. However, when ^•O₂⁻ is used as an oxidant, it promotes the generation of H₂O₂, while SOD prevents chain reactions initiated by ^•O₂⁻ oxidation and reduces the generation of H₂O₂ (Liochev and Fridovich, 1994).

ROS are well established as playing dual roles as harmful and beneficial components. Overproduction of ROS can induce cell death via signaling pathways such as autophagy and apoptosis, resulting in oxidative stress. However, ROS at low or moderate concentrations will exert beneficial effects involving multiple cellular signaling pathways and playing various physiological roles (Valko et al., 2007). Inflammation is a defensive immune response to stimuli, where phagocytes and endothelial cells play a central role and contain ROS generated by NADPH oxidase. Neutrophils also produce ROS that can promote inflammatory cell migration to clear foreign materials and pathogens but this also results in host tissue damage (Mittal et al., 2014). Xanthine oxidoreductase is transformed by proteases into xanthine oxidase, which is then able to transfer electrons from xanthine to oxygen to generate ROS and participate in the inflammatory pathway by inactivating MAPK phosphatase-1, leading to JNK phosphorylation in macrophages (Nomura et al., 2013). Parthanatos, also known as poly ADP-ribose polymerase-1 (PARP-1)-dependent cell death, is a newly described form of programmed brain cell death. JNK phosphorylation promotes oxidative stress-induced parthanatos by increasing intracellular ROS generation (Zheng et al., 2017).

Oxidative stress is associated with several human diseases, including diabetes, cancer, neurodegenerative diseases, cardiovascular diseases, and aging (Aruoma et al., 2006; Milkovic et al., 2014). Increased ROS production leads to disturbances in the balance between oxidation and the antioxidant defense system of the body, causing oxidative stress and this has been observed in cancer cells (Trachootham et al., 2009). Cancer cells exhibit high levels of ROS owing to aberrant signaling, which may be an obstacle to tumor generation. However, ROS can also accelerate tumor growth via oncogenic signaling pathways, DNA mutations, and DNA damage (Ames, 1983; Gorrini et al., 2013). DNA mutations are crucial for tumor formation. With the accumulation of ROS, the number of cellular mutations increases, and DNA is constantly damaged. The product of the direct reaction of •OH with guanosine is 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), which is moderately mutagenic and affects G→T transversion mutations (Fleming and Burrows, 2017). 8-oxo-dG can be an indicator of cellular oxidative stress, with its presence suggesting increased oxidative stress and tumor malignancy. Therefore, the modulation of ROS levels plays a significant role in potential anticancer strategies. Most cancer cells exhibit multiple genetic alterations, increased ROS generation, and altered redox status with additive oxidative stress and aerobic glycolysis, suggesting that preferential clearance of these cells by modulation of the redox modulation mechanism may be a valid strategy for cancer therapy (Trachootham et al., 2009).

Pathogenesis of gliomas

Gliomas are among the most common malignant brain tumors in adults, accounting for more than 70% of which glioblastoma (GBM) is the most malignant form. GBM accounts for 14.3% of all tumors and 49.1% of malignant tumors (Ostrom et al., 2021). The updated 2016 edition of the World Health Organization (WHO) classification of CNS tumors was the first to use molecular type and histology to define major tumor categories (Louis et al., 2016). This classification divides gliomas into four grades. Grade I mainly includes angiocentric gliomas and pilocytic astrocytomas. Grade II includes diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas. Grade III includes anaplastic astrocytomas. Finally, grade IV tumors include GBM and gliosarcomas. Traditionally, low-grade gliomas (LGGs) include grade I and grade II gliomas and high-grade gliomas (HGGs) include grade III and grade IV gliomas. However, the fifth edition of the CNS classification adopted in 2021 introduced new types and subtypes of gliomas based on molecular biomarkers (Louis et al., 2021). Currently, the standard treatment for newly diagnosed HGGs is surgical resection within a feasible range, followed by adjuvant radiotherapy (60 Gy/2 Gy/30 f) and concurrent oral temozolomide (TMZ) from the first day of radiotherapy to the last day. Sequential chemotherapy with six cycles of adjuvant temozolomide (Tan et al., 2020). The prognosis of patients with gliomas remains poor despite standard radiotherapy and TMZ treatment. Almost all patients with GBM show disease progression after a median progression-free survival of 7–10 months. Besides radiotherapy and chemotherapy, molecular-targeted therapy is widely used, especially in recurrent gliomas, and holds the promise of providing more effective treatment options with minimal toxicity (Omuro and DeAngelis, 2013). Immunotherapy clears tumors via antitumor responses by the host immune system, releases antigens, regulates immune pathways, and elicits tumor-specific cytotoxic T-cells, eventually resulting in immunogenic death (Liu et al., 2021). Despite the current advent of multiple immunotherapies, they have not significantly improved the overall survival of patients with glioma, which is associated with a suppressive immune microenvironment in glioma cells. Immunosuppression of gliomas is associated with multiple biological processes, such as aerobic glycolysis, tryptophan metabolism, and arginine metabolism (Chen and Hambardzumyan, 2018). Multiple mechanisms by which glioma cells evade detection and destruction in the immune system include T-cell, NK cell, and myeloid dysfunction; M2 phenotypic conversion in tumor-associated macrophages/microglia; glioma cell cytokine and surface factor cytokine upregulation; and glioma cell microenvironment hypoxia (Grabowski et al., 2021).

Gliomas are complex microcosms that depend on growth regulatory signals sent by the tumor microenvironment and feature angiogenesis and redox state changes. Communication between non-neoplastic and neoplastic cells contributes to the formation, progression, and response to cancer treatments. Receptors on glioma cells bind to ligands secreted by normal brain parenchymal cells, which may promote glioma invasion or create a microenvironment for malignant progression (Hoelzinger et al., 2007). In addition, abnormal activation of the inflammatory response is a characteristic of GBM and inflammation can promote tumor growth and resistance to treatment (Ham et al., 2019). High ROS levels lead to the death of astrocytes through necrosis and apoptosis, affecting the degree of malignancy via the nuclear factor kappa enhancer-binding protein (NF-κB) (Waris and Ahsan, 2006). Cancer development is a multi-stage process described in three stages: initiation, promotion, and progression. The initiation stage involves a non-lethal mutation in the DNA. The promotion phase is a reversible process characterized by the initiation of clonal expansion of cells through the induction of cell proliferation or inhibition of programmed cell death (i.e., apoptosis). At this stage, it is necessary to continue the existence of the tumor to promote stimulation. The final stage of carcinogenesis is irreversible and involves genetic instability and damage to chromosome integrity. The accumulation of additional genetic damage, vascularization, invasion, and metastasis leads to the transformation of cells from benign to malignant, which means that benign preneoplastic lesions become neoplastic cancer cells (Valko et al., 2006).

Oxidative stress is particularly important in glioma pathogenesis. The nervous system is vulnerable to oxidative stress because of high oxygen metabolism in the brain (Barciszewska et al., 2019). ROS-induced oxidative stress leads to DNA damage, which affects the proliferation and apoptosis of glioma cells and increases their susceptibility to gliomas. Human MutT homolog protein 1 (hMTH1) is an enzyme that hydrolyzes 8-oxo-dGTP to the corresponding monophosphate and prevents 8-oxo-dG from accumulating in DNA. The level of oxidative stress is higher in HGGs, therefore, the accumulation of 8-oxo-dG and the expression of hMTH1 are more pronounced. Enhancing the defense against this oxidative stress could be used to treat tumors (Iida et al., 2001). A case-control study showed that the influence of antioxidant gene variations, such as SOD3 T58A, SOD2 V16A, NOS1 3′-UTR, and GPX1-46 C/T, was correlated with the risk of glioma development (Zhao et al., 2012). A study investigated the possible pathway by which H₂O₂ induced apoptosis in glioma cells and concluded that oxidative stress inhibited glioma cell growth and induced apoptosis via a caspase-3-dependent pathway (Liu et al., 2015). Glioma stem-like cells (GSCs) are a class of subpopulations with stem-like characteristics in glioma cells that confer self-renewal capacity and therapeutic resistance (Mittal et al., 2014). ROS is crucial for the study of therapeutic strategies for GSCs. GSCs, like normal stem cells, maintain low ROS levels, which is in contrast to the high ROS levels in cancer cells (Mittal et al., 2014).

Functional annotation analysis of differentially methylated genes in pediatric GBM and adult GBM identified ROS regulation as a vital process in pediatric GBM and ROS-related genes neutrophil cytosolic factor 1 (NCF1) and NOX4 are upregulated and play important roles in chemosensitivity and proliferation (Jha et al., 2014).

The mechanism of oxidative stress modulators in gliomas

The design of many molecular targets based on oxidative stress is essential for maximizing survival and transforming this treatment into a form of precision medicine. The following section describes several therapeutic targets that influence oxidative stress.

Oxidative stress activates multiple transcription factors, including hypoxia-inducible factor-1α (HIF-1α), AP-1, NF-κB, p53, and nuclear factor erythroid 2-related factor 2 (Nrf2) (Reuter et al., 2010). Nrf2 is an important component of the cellular defense against various exogenous and endogenous stresses that can be activated in response to a series of oxidative and electrophilic stimulations (Kensler et al., 2007). Nrf2 serves as a potential therapeutic target in gliomas since activating its expression will increase the content of target antioxidants and enzymes that protect cells from apoptosis, whereas inhibiting its expression can elevate the killing effects of antitumor therapies (Zhu et al., 2014). Kelch-like ECH-associated protein 1 (KEAP1) is an inhibitor of Nrf2, which acts by modulating Nrf2 activity. A complex consisting of Cullin 3 (Cul3), KEAP1, and ring-box 1 (RBX1) binds to E2 ubiquitin-conjugating enzyme, and Nrf2 and Nedd8 (N8) induce a conformational change that inhibits Nrf2 ubiquitination (Baird and Yamamoto, 2020). Upon recognition of oxidative stress, Nrf2 dissociates from KEAP1, translocates to the nucleus, and heterodimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs). Nrf2 and other transcription factors regulate the expression of antioxidant genes by interacting with antioxidant response elements (ARE) (Reuter et al., 2010). The KEAP1–Nrf2–ARE signaling pathway plays a significant role in protecting cells from oxidative stress. Oxidative stress-related molecules and matrix metalloproteinases (MMPs) are involved in regulating glioma migration and invasion via the Nrf2/ARE pathway (Deryugina et al., 1997). Downregulation of Nrf2 expression can inactivate MMP-9 and reduce the migration and invasion of gliomas (Pa n et al., 2013). Heme oxygenase-1 (HO-1), a downstream molecule of Nrf2, plays a key role in regulating oxidative stress. Nuclear Nrf2 upregulates HO-1 and decreases intracellular ROS (Kanzaki et al., 2013). HO-1, which is involved in heme metabolism, catalyzes the conversion of heme to biliverdin and generates carbon monoxide during this process (Hayashi et al., 1999). HO-1 protein expression is associated with the degree of glioma malignancy and is overexpressed in HGGs. Moreover, HO-1 participates in immune cell infiltration and is associated with metastasis and angiogenesis. The mechanism of action of Nrf2 in glioma treatment is shown in Figure 2.

FIGURE 2

HIF-1 is a DNA-binding protein and is composed of two different subunits, 120 kDa HIF-1α and 91–94 kDa HIF-1β (Wang and Semenza, 1995). HIF-1 allows tumor cells to survive in the absence of oxygen, activating the transcription of glycolytic enzymes, glucose transporters, and vascular endothelial growth factors (Zhong et al., 1999). ROS can alter the function and activity of HIF-1 and inhibition of HIF-1 activity contributes to tumor therapy. NOX4 mRNA expression levels in GBM are markedly higher than those in other astrocytomas (Shono et al., 2008). A previous study revealed that circulating hypoxic conditions increase ROS production, activate HIF-1, and promote the growth of glioma cells by upregulating the expression of NOX4 mRNA and protein expression in GBM cells (Hsieh et al., 2011). NOX2, a downstream target gene of microRNA (miR)-34a, increases ROS levels and promotes apoptosis in glioma cells (Li et al., 2014). Therefore, knockdown of NOX2 and NOX4 during GBM progression may be a therapeutic method for counteracting the effect of hypoxia on tumor progression.

A study identified that diacylglycerol O-acyltransferase 1 (DGAT1) is highly expressed in HGGs. Inhibition of DGAT1 was shown to significantly upregulate the carnitine palmitoyltransferase 1A (CPT1A) protein, which facilitates the entry of excessive fatty acids (FAs) into the mitochondria for oxidation, resulting in mitochondrial damage, remarkable increase in GBM cell apoptosis, and ROS production (Cheng et al., 2020). Therefore, targeting DGAT1 may be a potential therapeutic approach for glioma treatment.

Epidermal growth factor receptor (EGFR) induces protein kinase Cε (PKCε) to phosphorylate and activate IκB kinase β (IKKβ) at Ser177, increasing the expression of pyruvate kinase M2 (PKM2). NF-κB is also involved in this process (Yang et al., 2012a). EGFR also induces ERK2 to phosphorylate PKM2 at Ser 37, which allows peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) to bind to PKM2, prompting PKM2 to translocate to the nucleus, upregulating lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) expression and promoting the Warburg effect (Yang et al., 2012b). A previous study indicated that the expression of PKM2 is correlated with the grade of glioma malignancy and that the level of PKM2 is lower in LGGs than in HGGs (Yang et al., 2012a). The heat shock protein (HSP) 90–PKM2–B-cell lymphoma 2 (Bcl2) axis is a potential therapeutic target in GBM treatment. In cancer cells, PKM2 affects ROS levels in two ways (Liang et al., 2017). Firstly, oxidative stress induces PKM2 translocation to the mitochondria where it phosphorylates Bcl2 at Thr69 site with the help of the chaperone protein HSP90α1. This prevents the combination of Cul3-based E3 ligase and Bcl2, thereby maintaining the stability of Bcl2 and increasing the resistance of glioma cells to oxidative stress-induced apoptosis. Researchers have also found that the PKM2 389–405 peptide is an efficacious medicine that disrupts the interaction between PKM2-Bcl2 leading to an antitumor effect that hinders the development of gliomas. Secondly, Cys358 oxidation inhibits PKM2 activity, thereby activating the ROS scavenging system in response to increased ROS levels. Collectively these results indicate that PKM2 could be a potential target for developing effective treatment of GBM. The mechanism underlying PKM2 regulation is shown in Figure 3.

FIGURE 3

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was recently identified as a novel cancer target. PTPN2 is oxidized and inactivated by H₂O₂ and the expression levels of PTPN2 are increased in GBM and isocitrate dehydrogenase (IDH) wild-type gliomas. An increase in PTPN2 levels is correlated with a worse overall survival rate (Wang et al., 2018). Furthermore, another study observed this phenomenon, indicating that oxidative stress may be exploited to stimulate PTPN2 inactivation for treating gliomas (Wu et al., 2019).

Prohibitin (PHB) is a highly conserved pleiotropic protein that plays a vital role in multiple biological processes. Peroxiredoxin3 (PRDX3) is a specific peroxidase in the mitochondria that scavenge peroxides and protects cells from oxidative stress. PHB binds to and stabilizes PRDX3 to inhibit mitochondrial ROS accumulation and promote GSCs self-renewal. Therefore, knockout of the PHB gene significantly increases ROS levels and inhibits GSCs self-renewal (Huang et al., 2021).

The oncostatin M receptor (OSMR) is a direct signal transducer and activator of the transcription 3 (STAT3) target gene, a member of the IL-6 receptor family, and is involved in many cellular responses, such as differentiation, proliferation, and survival. The depletion of OSMR affects EGFRvIII–STAT3 signaling and significantly retards the proliferation of GBM cells, prolonging their lifespan (Jahani-Asl et al., 2016). A study examined the relationship between ROS and OSMR and found interaction with nicotinamide adenine dinucleotide (NADH) ubiquinone oxidoreductase 1/2 (NDUFS1/2). Deleting OSMR promotes the generation of ROS, sensitizes GBM cells to radiotherapy, and induces glioma cell death (Sharanek et al., 2020). It is possible to identify drugs that inhibit OSMR expression to achieve the goal of treating gliomas.

Paired box 6 (PAX6) is a DNA-binding transcription factor that downregulates the expression of the vascular endothelial growth factor A (VEGFA) gene in glioma cells to suppress tumor cell invasion. PAX6 expression was found to be significantly reduced in GBM compared to LGGs. It has been shown that GBM cells with lower PAX6 levels survive better in a stressful environment after detachment from the culture. ROS levels increased following cell detachment and the addition of antioxidants enhanced the viability of PAX6-overexpressing cells, however, this did not recover their proliferative capacity (Chang et al., 2007).

A study that utilized proteomic analysis of cells from patients with GBM revealed that the autocrine factor midkine (MDK) promotes cell proliferation and detoxifies ROS. Inhibition of MDK expression may serve as a novel approach for GBM treatment by inducing ROS-mediated apoptosis and cell cycle arrest (Han et al., 2019).

Proteomics suggests that HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is associated with mitochondrial function, and knockdown of HOTAIRM1 can increase the level of ROS and radiation sensitivity, thereby prolonging patient survival (Ahmadov et al., 2021).

Apurinic/apyrimidinic endonuclease1 (APE1), associated with checkpoint kinase 2 (Chk2), participates in the coordination of double-strand break DNA repair. Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secreted protein that possesses lysophospholipase D activity and hydrolyzes pyrophosphate bonds and phosphodiesters from various substrates (Amaral et al., 2021). Oxidative stress elevates the expression levels of APE1 and PKM2 and stimulates the extracellular secretion and intracellular expression of ENPP2 in glioma cells (Cholia et al., 2018). These results revealed that glioma progression is mediated by the regulation of activity, expression levels, and the correlation of these three enzymes. Sirtuin 6 (SIRT6) is a nuclear NAD⁺-dependent histone H3 deacetylase that regulates its genomic expression and stability. An experiment revealed that mir-33a reduced ROS levels by inhibiting SIRT6 expression and decreasing cell survival following H₂O₂ treatment (Chang et al., 2017). SIRT6 suppresses the oxidative stress response while inhibiting Janus kinase 2 (JAK2)/STAT3 signaling pathway activation during glioma treatment (Feng et al., 2016). Recent studies on the target genes that influence oxidative stress in gliomas are summarized in Table 1.

The efficacy of phytocompounds in gliomas

Several studies have emphasized the relationship between oxidative stress and the emergence of drugs. However, many drugs are unable to cross the blood–brain barrier (BBB) to achieve maximum therapeutic efficacy. The BBB is composed of capillary endothelial cells, an intact basement membrane, and glial membranes surrounding astrocyte foot plates and is a barrier between the walls of brain capillaries and plasma to brain cells formed by glial cells. The BBB excludes substances that are hazardous to the brain, protects the brain from harm, and allows particles smaller than 20 nm in diameter to cross over (Abbott et al., 2010). If a drug is converted into a small molecule, it can pass through the BBB to achieve the purpose of treatment.

Quinoxaline-1,4-dioxide derivatives are a class of synthetic heterocyclic compounds that exhibit diverse biological and pharmacological effects. They can promote cell damage by increasing ROS (Silva et al., 2019). Thymoquinone (TQ) is a drug that can penetrate the BBB and act against gliomas through its antioxidant, antimetastatic, and anti-invasive activities (Racoma et al., 2013). TQ regulates the production of superoxide in mitochondria in a dose-dependent manner and low-dose TQ inhibits superoxide production in mitochondria. ROS generation has been shown to increase with higher TQ concentrations. It has also been confirmed that TQ induces apoptosis in C6 glioma cells via redox-dependent MAPK proteins (Krylova et al., 2019). This provides direction for treatment options for gliomas.

Chidamide is a histone deacetylase (HDAC) inhibitor that selectively inhibits the activity of HDAC1, 2, 3, and 10 (Shi et al., 2017). The Hedgehog (Hh) signaling pathway affects glioma growth. This pathway is initiated by a combination of Patched and Hh proteins, consisting of Sonic Hh (Shh), Desert Hh, and Indian Hh (Ihh), which allows Smoothened to transmit signals to the nucleus. A basic study suggested that chidamide inactivates Hh signaling by increasing the level of miR-338-5p, increasing oxidative stress and promoting glioma cell apoptosis and necrosis (Zhou et al., 2020). Chidamide could therefore be used as a potential drug to prevent glioma development.

A review summarized that combining antiparasitic drugs, such as ivermectin, atovaquone, proguanil, quinacrine, and mefloquine with radiotherapy could potentially enhance the radiosensitivity of HGGs by abolishing tumor hypoxia and enhancing oxidative stress (Mudassar et al., 2020). In conclusion, the combination of radiotherapy and antiparasitic drugs may be a new method for the treatment of malignant HGGs and may improve patient survival.

Quercetin (Qu), a plant-derived flavonoid, is known for its anti-tumor and anti-proliferative activities. Qu has been modified as a chemoprotective and radiosensitive agent that plays an important role in the treatment of GBM, and it has been found to inhibit oxidative stress by scavenging ROS to achieve antitumor effects (Tavana et al., 2020).

One study examined the antitumor effects of eight Cu(II) complexes with uracil-functionalized ligands in glioma cells. These compounds promoted apoptosis and autophagy in glioma cells by affecting the activities of SOD and CAT (Illán-Cabeza et al., 2020). Thus, copper (II) complexes can be used as drugs to manipulate the redox microenvironment to treat gliomas.

Melatonin, a free-radical scavenger, exerts antioxidant effects and protects the BBB under hypoxic conditions. Melatonin has been shown to significantly reduce the invasion and migration of glioma cells by inhibiting the ROS/NF-κB/MMPs pathway (Wang et al., 2012). This indicates that melatonin has potential therapeutic applications for the treatment of gliomas.

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis by binding to receptors that contain death domains. The fungal metabolite chaetocin is a novel TRAIL sensitizer and is an inhibitor of the histone methyltransferase SUV39H1. Chaetocin promotes apoptosis by depleting the expression of heme oxygenase 1 (HMOX1) thereby inducing ROS-dependent apoptosis (Ozy erli-Goknar et al., 2019). The increase in ROS can also affect the apoptosis and metabolism of glioma cells via the JNK-regulated metabolic pathway and ataxia telangiectasia mutated (ATM)-Yes-associated protein 1 (YAP1)-driven apoptotic pathway (Dixit et al., 2014). These results provide a basis for the combination of chaetocin and TRAIL for the treatment of gliomas.

Celastrol is one of the most important active ingredients of the traditional Chinese medicine Tripterygium wilfordii, which activates the JNK pathway and ROS production and inhibits the activities of mechanistic targets of rapamycin (mTOR) and Akt kinases, significantly increasing apoptosis and autophagy in glioma cells (Liu et al., 2019).

Osthole is a coumarin derived from traditional Chinese medicine. One study found that osthole is a potential drug for treating gliomas, as it increases the production of ROS and upregulates the expression of induced receptor interacting protein kinase 1 (RIP1), RIP2, and mixed lineage kinase domain-like protein (MLKL). These results confirm that osthole induces mitochondrial depolarization and necroptosis (Huangfu et al., 2021).

Shikonin, a naphthoquinone, has been studied as a preventive or therapeutic drug for the treatment of gliomas. Shikonin dose-dependently induces ROS overproduction in glioma cells and upregulates RIP1 and RIP3 to mediate necroptosis (Lu et al., 2017).

Small molecule antioxidants containing selenium can ameliorate oxidative damage. Selenocysteine (SeC), a naturally available selenoamino acid that potentiates the production of ROS and superoxide anions, induces DNA damage, causes S-phase cell cycle arrest, and inhibits the growth of glioma cells (Wang et al., 2016).

An experiment revealed that polyphyllin VI (PPVI), a bioactive ingredient extracted from the traditional Chinese medicine Paris polyphylla, increases ROS accumulation, which in turn activates ROS-regulated JNK and p38 pathways and regulates the G2/M phase to inhibit glioma cell proliferation (Liu et al., 2020). Thus, PPVI might be a potential therapeutic agent for gliomas.

Deoxypodophyllotoxin (DPT), isolated from herbal plants, is used as a precursor for teniposide and etoposide phosphate. Overproduction of DPT triggers ROS-induced upregulation of PARP-1, which promotes apoptosis-inducing factor (AIF) translocation into the nucleus, causing parthanatos in glioma cells (Ma et al., 2016). This study provides novel insights for the development of an anti-glioma strategy.

Cannabidiol (CBD) is a non-psychoactive, natural ingredient extracted from cannabis. CBD has proapoptotic and antiproliferative effects and serves an anti-glioma purpose by increasing the production of ROS and the activity of GSH-associated enzymes, as well as depleting glutathione (Massi et al., 2006). Another study found a similar view that CBD induces a substantial increase in ROS, thereby inhibiting GSCs survival and self-renewal (Singer et al., 2015).

Proteomic analysis of cells following treatment with loperamide and pimozide revealed that these drugs can induce endoplasmic reticulum stress, leading to increased ROS levels and promoting cell death (Meyer et al., 2021).

Silibinin is a polyphenolic extract of Silybum marianum. Silibinin suppresses glycolysis in tumor cells, thereby activating autophagy. Autophagy increases H₂O₂ levels by promoting p53-mediated GSH depletion and inducing Bcl2 interacting protein 3 (BNIP3) upregulation, mitochondrial damage, and AIF translocation from the mitochondria to the nucleus, resulting in glioma cell death (Wang et al., 2020). Therapeutic agents that regulate ROS levels to provide new ideas for glioma treatment are summarized in Table 2. And the effect and pathway of these therapeutic agents pertinent to ROS are shown in Figure 4.

FIGURE 4

Effect of radiotherapy and chemotherapy on oxidative stress in gliomas

Radiotherapy and chemotherapy, as standard treatment strategies, have been rapidly developed and are widely used in clinics to eliminate gliomas. However, resistance to radiation and chemotherapeutic drugs is a fundamental obstacle to improving the curative effect of gliomas. Therefore, the design and development of novel chemoradiotherapy strategies to overcome resistance have become a focus of clinical oncology research. Gliomas need to use radiotherapeutic or chemotherapeutic drugs to influence the prognosis through ROS modulation. A study demonstrated that combined treatment with radiation and salinomycin (SAL) increased DNA damage and tumor apoptosis by increasing ROS production, which is a novel strategy to improve the efficacy of radiotherapy in cancer prevention and overcome radioresistance (Liu et al., 2018). The radioresistance of human glioma cells induced by SOD1 overexpression is related to the inhibition of late ROS accumulation and enhancement of G2/M accumulation (Gao et al., 2008). Another study revealed that adenosine triphosphate (ATP) channels can control glioma radioresistance by adjusting ROS-induced ERK activation; thus, inhibiting ATP channels is a potential target for glioma therapeutic development (Huang et al., 2015). One way to increase radiosensitivity is to increase intracellular ROS by 5-aminolevulinic acid treatment, which results in the radiosensitization of glioma cells (Kitagawa et al., 2015). The transcriptional activity of the HIF-1 signal induced by ROS in cyclic hypoxia was higher than that in intermittent hypoxia. Under hypoxic conditions, knockout of the HIF-1 gene inhibits uninterrupted hypoxia-induced radioresistance while increasing the overall radiosensitivity of the tumor (Hsieh et al., 2010). Outer-membrane vesicles (OMVs) from Escherichia coli and gold nanoparticles (AuNPs) were combined to synthesize Au-OMVs. Combining Au-OMVs with radiotherapy generated ROS to increase radiosensitization and suppress glioma cell growth (Chen et al., 2021). Proton beam radiation generates substantial amounts of ROS, which induces cell cycle redistribution and DNA damage and promotes apoptosis in GSCs (Alan Mitteer et al., 2015). The main adverse effect is a radiation-induced skin reaction, with its mechanisms including inflammation and oxidative stress, which interact and promote each other. Direct exposure of normal cells to radiation or ROS may lead to apoptosis and necrosis, which triggers the release of anti-inflammatory cytokines (Wei et al., 2019).

During chemotherapy, when O⁶-methylguanine methyltransferase, alkylpurine-DNA-N-glycosylase, and base excision repair proteins are expressed, GBM cells are resistant to TMZ (Lee, 2016). Drug efflux transporters, the advent of GSCs, and the upregulation of autophagy are also mechanisms of TMZ resistance (Tomar et al., 2021). The curcumin analog ALZ003 increased the production of ROS and ubiquitinated the androgen receptor resulting in its degradation, which potentiated TMZ resistance. This result provides evidence to improve the efficacy in glioma patients resistant to TMZ (Chen et al., 2020). Gemcitabine combined with nanomaterials, such as AgNTs, participates in ROS-dependent mitochondrial pathway-mediated apoptosis, thereby inhibiting the activity of gliomas, indicating that AgNTs and chemotherapeutics have a synergistic effect (Yang et al., 2020). Dimethylaminomicheliolide is a novel chemotherapeutic agent that induces apoptosis and autophagy by adjusting the ROS/MAPK signaling pathway and inhibiting the Akt/mTOR signaling pathway to treat gliomas (Wang et al., 2019).

Conclusion

Gliomas are highly malignant and prone to recurrence and progression. Although a certain degree of therapeutic effect can be achieved by applying standard treatment methods, the prognosis remains unsatisfactory. Oxidative stress has an important role in the occurrence and development of glioma, as well as in treatment. Therefore, antioxidative therapy can be considered a new therapeutic strategy for the treatment of gliomas. By summarizing the components of ROS, the role of oxidative stress in gliomas pathogenesis, the effects of oxidative stress on targets such as Nrf2, NOX2, NOX4, DGAT1, PKM2, PTPN2, PHB, OSMR, and PAX6 are presented in this paper, and some phytochemicals shown to alter glioma cell growth by affecting oxidative stress are discussed. Moreover, we suggest potential targets and drugs that modify radiosensitivity and chemoresistance by affecting oxidative stress, all of which provide new directions for our enriched treatment regimens for gliomas. However, extensive basic experimental and clinical trial research are still needed to explore the selection of intervention time and dosage of drugs. In addition, the efficacy of combining antioxidant treatment with other treatments also deserves to explore.

References

• 1

  AbbottN. J.PatabendigeA. A.DolmanD. E.YusofS. R.BegleyD. J. (2010). Structure and function of the blood-brain barrier. Neurobiol. Dis.37, 13–25. 10.1016/j.nbd.2009.07.030

  • CrossRef
  • Google Scholar

• 2

  AhmadovU.PicardD.BartlJ.SilginerM.Trajkovic-ArsicM.QinN.et al (2021). The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma. Cell Death Dis.12, 885. 10.1038/s41419-021-04146-0

  • CrossRef
  • Google Scholar

• 3

  Alan MitteerR.WangY.ShahJ.GordonS.FagerM.ButterP. P.et al (2015). Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species. Sci. Rep.5, 13961. 10.1038/srep13961

  • CrossRef
  • Google Scholar

• 4

  AmaralR. F.GeraldoL. H. M.Einicker-LamasM.TclsE. S.MendesF.LimaF. R. S.et al (2021). Microglial lysophosphatidic acid promotes glioblastoma proliferation and migration via LPA(1) receptor. J. Neurochem.156, 499–512. 10.1111/jnc.15097

  • CrossRef
  • Google Scholar

• 5

  AmesB. N. (1983). Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science221, 1256–1264. 10.1126/science.6351251

  • CrossRef
  • Google Scholar

• 6

  AruomaO. I.GrootveldM.BahorunT. (2006). Free radicals in biology and medicine: From inflammation to biotechnology. Biofactors27, 1–3. 10.1002/biof.5520270101

  • CrossRef
  • Google Scholar

• 7

  BairdL.YamamotoM. (2020). The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol. Cell. Biol.40, e00099–20. 10.1128/MCB.00099-20

  • CrossRef
  • Google Scholar

• 8

  BarciszewskaA. M.Giel-PietraszukM.PerrigueP. M.Naskręt-BarciszewskaM. (2019). Total DNA methylation changes reflect random oxidative DNA damage in gliomas. Cells8, E1065. 10.3390/cells8091065

  • CrossRef
  • Google Scholar

• 9

  BehrendL.HendersonG.ZwackaR. M. (2003). Reactive oxygen species in oncogenic transformation. Biochem. Soc. Trans.31, 1441–1444. 10.1042/bst0311441

  • CrossRef
  • Google Scholar

• 10

  BetteridgeD. J. (2000). What is oxidative stress?Metabolism49, 3–8. 10.1016/s0026-0495(00)80077-3

  • CrossRef
  • Google Scholar

• 11

  BrownD. I.GriendlingK. K. (2009). Nox proteins in signal transduction. Free Radic. Biol. Med.47, 1239–1253. 10.1016/j.freeradbiomed.2009.07.023

  • CrossRef
  • Google Scholar

• 12

  BurtenshawD.KitchingM.RedmondE. M.MegsonI. L.CahillP. A. (2019). Reactive oxygen species (ROS), intimal thickening, and subclinical atherosclerotic disease. Front. Cardiovasc. Med.6, 89. 10.3389/fcvm.2019.00089

  • CrossRef
  • Google Scholar

• 13

  ChangJ. Y.HuY.SiegelE.StanleyL.ZhouY. H. (2007). PAX6 increases glioma cell susceptibility to detachment and oxidative stress. J. Neurooncol.84, 9–19. 10.1007/s11060-007-9347-x

  • CrossRef
  • Google Scholar

• 14

  ChangM.QiaoL.LiB.WangJ.ZhangG.ShiW.et al (2017). Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance. Oncol. Rep.38, 1251–1258. 10.3892/or.2017.5780

  • CrossRef
  • Google Scholar

• 15

  ChenD.FanZ.RauhM.BuchfelderM.EyupogluI. Y.SavaskanN.et al (2017). ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene36, 5593–5608. 10.1038/onc.2017.146

  • CrossRef
  • Google Scholar

• 16

  ChenM. H.LiuT. Y.ChenY. C.ChenM. H. (2021). Combining augmented radiotherapy and immunotherapy through a nano-gold and bacterial outer-membrane vesicle complex for the treatment of glioblastoma. Nanomater. (Basel)11, 1661. 10.3390/nano11071661

  • CrossRef
  • Google Scholar

• 17

  ChenT. C.ChuangJ. Y.KoC. Y.KaoT. J.YangP. Y.YuC. H.et al (2020). AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis. Redox Biol.30, 101413. 10.1016/j.redox.2019.101413

  • CrossRef
  • Google Scholar

• 18

  ChenZ.HambardzumyanD. (2018). Immune microenvironment in glioblastoma subtypes. Front. Immunol.9, 1004. 10.3389/fimmu.2018.01004

  • CrossRef
  • Google Scholar

• 19

  ChengX.GengF.PanM.WuX.ZhongY.WangC.et al (2020). Targeting DGAT1 ameliorates glioblastoma by increasing fat catabolism and oxidative stress. Cell Metab.32, 229–242. e8. 10.1016/j.cmet.2020.06.002

  • CrossRef
  • Google Scholar

• 20

  CholiaR. P.DhimanM.KumarR.ManthaA. K. (2018). Oxidative stress stimulates invasive potential in rat C6 and human U-87 MG glioblastoma cells via activation and cross-talk between PKM2, ENPP2 and APE1 enzymes. Metab. Brain Dis.33, 1307–1326. 10.1007/s11011-018-0233-3

  • CrossRef
  • Google Scholar

• 21

  De DuveC.BaudhuinP. (1966). Peroxisomes (microbodies and related particles). Physiol. Rev.46, 323–357. 10.1152/physrev.1966.46.2.323

  • CrossRef
  • Google Scholar

• 22

  DeryuginaE. I.BourdonM. A.LuoG. X.ReisfeldR. A.StronginA. (1997). Matrix metalloproteinase-2 activation modulates glioma cell migration. J. Cell Sci.110 (Pt 19), 2473–2482. 10.1242/jcs.110.19.2473

  • CrossRef
  • Google Scholar

• 23

  DixitD.GhildiyalR.AntoN. P.SenE. (2014). Chaetocin-induced ROS-mediated apoptosis involves ATM-YAP1 axis and JNK-dependent inhibition of glucose metabolism. Cell Death Dis.5, e1212. 10.1038/cddis.2014.179

  • CrossRef
  • Google Scholar

• 24

  ErsozM.ErdemirA.DermanS.ArasogluT.MansurogluB. (2020). Quercetin-loaded nanoparticles enhance cytotoxicity and antioxidant activity on C6 glioma cells. Pharm. Dev. Technol.25, 757–766. 10.1080/10837450.2020.1740933

  • CrossRef
  • Google Scholar

• 25

  FengJ.YanP. F.ZhaoH. Y.ZhangF. C.ZhaoW. H.FengM.et al (2016). SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and suppression of JAK2/STAT3 signaling pathway activation. Oncol. Rep.35, 1395–1402. 10.3892/or.2015.4477

  • CrossRef
  • Google Scholar

• 26

  FlemingA. M.BurrowsC. J. (2017). 8-Oxo-7, 8-dihydroguanine, friend and foe: Epigenetic-like regulator versus initiator of mutagenesis. DNA Repair (Amst)56, 75–83. 10.1016/j.dnarep.2017.06.009

  • CrossRef
  • Google Scholar

• 27

  FlintD. H.EmptageM. H.FinneganM. G.FuW.JohnsonM. K. (1993). The role and properties of the iron-sulfur cluster in Escherichia coli dihydroxy-acid dehydratase. J. Biol. Chem.268, 14732–14742. 10.1016/s0021-9258(18)82394-8

  • CrossRef
  • Google Scholar

• 28

  FridovichI. (1997). Superoxide anion radical (O2-.), superoxide dismutases, and related matters. J. Biol. Chem.272, 18515–18517. 10.1074/jbc.272.30.18515

  • CrossRef
  • Google Scholar

• 29

  GaoZ.SarsourE. H.KalenA. L.LiL.KumarM. G.GoswamiP. C.et al (2008). Late ROS accumulation and radiosensitivity in SOD1-overexpressing human glioma cells. Free Radic. Biol. Med.45, 1501–1509. 10.1016/j.freeradbiomed.2008.08.009

  • CrossRef
  • Google Scholar

• 30

  GengY.KohliL.KlockeB. J.RothK. A. (2010). Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent. Neuro. Oncol.12, 473–481. 10.1093/neuonc/nop048

  • CrossRef
  • Google Scholar

• 31

  GerschmanR.GilbertD. L.NyeS. W.DwyerP.FennW. O. (1954). Oxygen poisoning and x-irradiation: A mechanism in common. Science119, 623–626. 10.1126/science.119.3097.623

  • CrossRef
  • Google Scholar

• 32

  GorriniC.HarrisI. S.MakT. W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov.12, 931–947. 10.1038/nrd4002

  • CrossRef
  • Google Scholar

• 33

  GrabowskiM. M.SankeyE. W.RyanK. J.ChongsathidkietP.LorreyS. J.WilkinsonD. S.et al (2021). Immune suppression in gliomas. J. Neurooncol.151, 3–12. 10.1007/s11060-020-03483-y

  • CrossRef
  • Google Scholar

• 34

  HalliwellB.GutteridgeJ. M. (1992). Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett.307, 108–112. 10.1016/0014-5793(92)80911-y

  • CrossRef
  • Google Scholar

• 35

  HamS. W.JeonH. Y.JinX.KimE. J.KimJ. K.ShinY. J.et al (2019). TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ.26, 409–425. 10.1038/s41418-018-0126-3

  • CrossRef
  • Google Scholar

• 36

  HanS.ShinH.LeeJ. K.LiuZ.RabadanR.LeeJ.et al (2019). Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target. Exp. Mol. Med.51, 1–11. 10.1038/s12276-019-0351-y

  • CrossRef
  • Google Scholar

• 37

  HayashiS.TakamiyaR.YamaguchiT.MatsumotoK.TojoS. J.TamataniT.et al (1999). Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: Role of bilirubin generated by the enzyme. Circ. Res.85, 663–671. 10.1161/01.res.85.8.663

  • CrossRef
  • Google Scholar

• 38

  HoelzingerD. B.DemuthT.BerensM. E. (2007). Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J. Natl. Cancer Inst.99, 1583–1593. 10.1093/jnci/djm187

  • CrossRef
  • Google Scholar

• 39

  HsiehC. H.LeeC. H.LiangJ. A.YuC. Y.ShyuW. C. (2010). Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity. Oncol. Rep.24, 1629–1636. 10.3892/or_00001027

  • CrossRef
  • Google Scholar

• 40

  HsiehC. H.ShyuW. C.ChiangC. Y.KuoJ. W.ShenW. C.LiuR. S.et al (2011). NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme. PLoS One6, e23945. 10.1371/journal.pone.0023945

  • CrossRef
  • Google Scholar

• 41

  HuangH.ZhangS.LiY.LiuZ.MiL.CaiY.et al (2021). Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance. Nat. Commun.12, 3720. 10.1038/s41467-021-24108-6

  • CrossRef
  • Google Scholar

• 42

  HuangL.LiB.TangS.GuoH.LiW.HuangX.et al (2015). Mitochondrial KATP channels control glioma radioresistance by regulating ROS-induced ERK activation. Mol. Neurobiol.52, 626–637. 10.1007/s12035-014-8888-1

  • CrossRef
  • Google Scholar

• 43

  HuangfuM.WeiR.WangJ.QinJ.YuD.GuanX.et al (2021). Osthole induces necroptosis via ROS overproduction in glioma cells. FEBS Open Bio11, 456–467. 10.1002/2211-5463.13069

  • CrossRef
  • Google Scholar

• 44

  IidaT.FurutaA.KawashimaM.NishidaJ.NakabeppuY.IwakiT. (2001). Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors. Neuro. Oncol.3, 73–81. 10.1093/neuonc/3.2.73

  • CrossRef
  • Google Scholar

• 45

  Illán-CabezaN. A.Jiménez-PulidoS. B.Hueso-UreñaF.Ramírez-ExpósitoM. J.Martínez-MartosJ. M.Moreno-CarreteroM. N.et al (2020). Relationship between the antiproliferative properties of Cu(II) complexes with the Schiff base derived from pyridine-2-carboxaldehyde and 5, 6-diamino-1, 3-dimethyluracil and the redox status mediated by antioxidant defense systems on glioma tumoral cells. J. Inorg. Biochem.207, 111053. 10.1016/j.jinorgbio.2020.111053

  • CrossRef
  • Google Scholar

• 46

  Jahani-AslA.YinH.SoleimaniV. D.HaqueT.LuchmanH. A.ChangN. C.et al (2016). Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat. Neurosci.19, 798–806. 10.1038/nn.4295

  • CrossRef
  • Google Scholar

• 47

  JhaP.Pia PatricI. R.ShuklaS.PathakP.PalJ.SharmaV.et al (2014). Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation. Neuro. Oncol.16, 1607–1617. 10.1093/neuonc/nou113

  • CrossRef
  • Google Scholar

• 48

  KanzakiH.ShinoharaF.KajiyaM.KodamaT. (2013). The Keap1/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling. J. Biol. Chem.288, 23009–23020. 10.1074/jbc.M113.478545

  • CrossRef
  • Google Scholar

• 49

  KenslerT. W.WakabayashiN.BiswalS. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol.47, 89–116. 10.1146/annurev.pharmtox.46.120604.141046

  • CrossRef
  • Google Scholar

• 50

  KitagawaT.YamamotoJ.TanakaT.NakanoY.AkibaD.UetaK.et al (2015). 5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: Quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro. Oncol. Rep.33, 583–590. 10.3892/or.2014.3618

  • CrossRef
  • Google Scholar

• 51

  KrylovaN. G.DrobyshM. S.SemenkovaG. N.KulahavaT. A.PinchukS. V.ShadyroO. I.et al (2019). Cytotoxic and antiproliferative effects of thymoquinone on rat C6 glioma cells depend on oxidative stress. Mol. Cell. Biochem.462, 195–206. 10.1007/s11010-019-03622-8

  • CrossRef
  • Google Scholar

• 52

  LeeS. Y. (2016). Temozolomide resistance in glioblastoma multiforme. Genes Dis.3, 198–210. 10.1016/j.gendis.2016.04.007

  • CrossRef
  • Google Scholar

• 53

  LeiK.GuX.AlvaradoA. G.DuY.LuoS.AhnE. H.et al (2020). Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma. J. Hematol. Oncol.13, 141. 10.1186/s13045-020-00979-y

  • CrossRef
  • Google Scholar

• 54

  LeiQ.LiuX.FuH.SunY.WangL.XuG.et al (2016). miR-101 reverses hypomethylation of the PRDM16 promoter to disrupt mitochondrial function in astrocytoma cells. Oncotarget7, 5007–5022. 10.18632/oncotarget.6652

  • CrossRef
  • Google Scholar

• 55

  LiS. Z.HuY. Y.ZhaoJ.ZhaoY. B.SunJ. D.YangY. F.et al (2014). MicroRNA-34a induces apoptosis in the human glioma cell line, A172, through enhanced ROS production and NOX2 expression. Biochem. Biophys. Res. Commun.444, 6–12. 10.1016/j.bbrc.2013.12.136

  • CrossRef
  • Google Scholar

• 56

  LiangJ.CaoR.WangX.ZhangY.WangP.GaoH.et al (2017). Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res.27, 329–351. 10.1038/cr.2016.159

  • CrossRef
  • Google Scholar

• 57

  LiochevS. I.FridovichI. (1994). The role of O2.- in the production of HO.: In vitro and in vivo. Free Radic. Biol. Med.16, 29–33. 10.1016/0891-5849(94)90239-9

  • CrossRef
  • Google Scholar

• 58

  LiuC.WangL.QiuH.DongQ.FengY.LiD.et al (2018). Combined strategy of radioactive (125)I seeds and salinomycin for enhanced glioma chemo-radiotherapy: Evidences for ROS-mediated apoptosis and signaling crosstalk. Neurochem. Res.43, 1317–1327. 10.1007/s11064-018-2547-2

  • CrossRef
  • Google Scholar

• 59

  LiuS.ZhaoQ.ShiW.ZhengZ.LiuZ.MengL.et al (2021). Advances in radiotherapy and comprehensive treatment of high-grade glioma: Immunotherapy and tumor-treating fields. J. Cancer12, 1094–1104. 10.7150/jca.51107

  • CrossRef
  • Google Scholar

• 60

  LiuW.ChaiY.HuL.WangJ.PanX.YuanH.et al (2020). Polyphyllin VI induces apoptosis and autophagy via reactive oxygen species mediated JNK and P38 activation in glioma. Onco. Targets. Ther.13, 2275–2288. 10.2147/OTT.S243953

  • CrossRef
  • Google Scholar

• 61

  LiuX. R.LiY. Q.HuaC.LiS. J.ZhaoG.SongH. M.et al (2015). Oxidative stress inhibits growth and induces apoptotic cell death in human U251 glioma cells via the caspase-3-dependent pathway. Eur. Rev. Med. Pharmacol. Sci.19, 4068–4075.

  • Google Scholar

• 62

  LiuX.ZhaoP.WangX.WangL.ZhuY.SongY.et al (2019). Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells. J. Exp. Clin. Cancer Res.38, 184. 10.1186/s13046-019-1173-4

  • CrossRef
  • Google Scholar

• 63

  LiuY.FangS.SunQ.LiuB. (2016). Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem. Biophys. Res. Commun.480, 415–421. 10.1016/j.bbrc.2016.10.064

  • CrossRef
  • Google Scholar

• 64

  LouisD. N.PerryA.ReifenbergerG.von DeimlingA.Figarella-BrangerD.CaveneeW. K.et al (2016). The 2016 world Health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol.131, 803–820. 10.1007/s00401-016-1545-1

  • CrossRef
  • Google Scholar

• 65

  LouisD. N.PerryA.WesselingP.BratD. J.CreeI. A.Figarella-BrangerD.et alThe 2021 WHO classification of tumors of the central nervous system: A summary. Neuro. Oncol.23 (2021), 1231–1251. 10.1093/neuonc/noab106

  • CrossRef
  • Google Scholar

• 66

  LuB.GongX.WangZ. Q.DingY.WangC.LuoT. F.et al (2017). Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. Acta Pharmacol. Sin.38, 1543–1553. 10.1038/aps.2017.112

  • CrossRef
  • Google Scholar

• 67

  MaD.LuB.FengC.WangC.WangY.LuoT.et al (2016). Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS. Cancer Lett.371, 194–204. 10.1016/j.canlet.2015.11.044

  • CrossRef
  • Google Scholar

• 68

  MassiP.VaccaniA.BianchessiS.CostaB.MacchiP.ParolaroD. (2006). The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell. Mol. Life Sci.63, 2057–2066. 10.1007/s00018-006-6156-x

  • CrossRef
  • Google Scholar

• 69

  McCordJ. M.FridovichI. (1969). Superoxide dismutase. J. Biol. Chem.244, 6049–6055. 10.1016/s0021-9258(18)63504-5

  • CrossRef
  • Google Scholar

• 70

  McKelveyK. J.WilsonE. B.ShortS.MelcherA. A.BiggsM.DiakosC. I.et al (2021). Glycolysis and fatty acid oxidation inhibition improves survival in glioblastoma. Front. Oncol.11, 633210. 10.3389/fonc.2021.633210

  • CrossRef
  • Google Scholar

• 71

  MeyerN.HenkelL.LinderB.ZielkeS.TascherG.TrautmannS.et al (2021). Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death. Autophagy17, 3424–3443. 10.1080/15548627.2021.1874208

  • CrossRef
  • Google Scholar

• 72

  MilkovicL.SiemsW.SiemsR.ZarkovicN. (2014). Oxidative stress and antioxidants in carcinogenesis and integrative therapy of cancer. Curr. Pharm. Des.20, 6529–6542. 10.2174/1381612820666140826152822

  • CrossRef
  • Google Scholar

• 73

  MittalM.SiddiquiM. R.TranK.ReddyS. P.MalikA. B. (2014). Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal.20, 1126–1167. 10.1089/ars.2012.5149

  • CrossRef
  • Google Scholar

• 74

  MudassarF.ShenH.O'NeillG.HauE. (2020). Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J. Exp. Clin. Cancer Res.39, 208. 10.1186/s13046-020-01724-6

  • CrossRef
  • Google Scholar

• 75

  NomuraJ.BussoN.IvesA.TsujimotoS.TamuraM.SoA.et al (2013). Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS One8, e75527. 10.1371/journal.pone.0075527

  • CrossRef
  • Google Scholar

• 76

  NosakaY.NosakaA. Y. (2017). Generation and detection of reactive oxygen species in photocatalysis. Chem. Rev.117, 11302–11336. 10.1021/acs.chemrev.7b00161

  • CrossRef
  • Google Scholar

• 77

  OmuroA.DeAngelisL. M. (2013). Glioblastoma and other malignant gliomas: A clinical review. Jama310, 1842–1850. 10.1001/jama.2013.280319

  • CrossRef
  • Google Scholar

• 78

  OstromQ. T.BauchetL.DavisF. G.DeltourI.FisherJ. L.LangerC. E.et al (2014). The epidemiology of glioma in adults: A "state of the science" review. Neuro. Oncol.16, 896–913. 10.1093/neuonc/nou087

  • CrossRef
  • Google Scholar

• 79

  OstromQ. T.CioffiG.WaiteK.KruchkoC.Barnholtz-SloanJ. S. (2021). CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro-oncology23, iii1–iii105. 10.1093/neuonc/noab200

  • CrossRef
  • Google Scholar

• 80

  Ozyerli-GoknarE.Sur-ErdemI.SekerF.CingözA.KayabolenA.Kahya-YesilZ.et al (2019). The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma. Cell Death Dis.10, 894. 10.1038/s41419-019-2107-y

  • CrossRef
  • Google Scholar

• 81

  PanH.WangH.ZhuL.MaoL.QiaoL.SuX.et al (2013). The role of Nrf2 in migration and invasion of human glioma cell U251. World Neurosurg.80, 363–370. 10.1016/j.wneu.2011.06.063

  • CrossRef
  • Google Scholar

• 82

  RacomaI. O.MeisenW. H.WangQ. E.KaurB.WaniA. A. (2013). Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One8, e72882. 10.1371/journal.pone.0072882

  • CrossRef
  • Google Scholar

• 83

  ReczekC. R.ChandelN. S. (2017). The two faces of reactive oxygen species in cancer. Annu. Rev. Cancer Biol.1, 79–98. 10.1146/annurev-cancerbio-041916-065808

  • CrossRef
  • Google Scholar

• 84

  ReuterS.GuptaS. C.ChaturvediM. M.AggarwalB. B. (2010). Oxidative stress, inflammation, and cancer: How are they linked?Free Radic. Biol. Med.49, 1603–1616. 10.1016/j.freeradbiomed.2010.09.006

  • CrossRef
  • Google Scholar

• 85

  SharanekA.BurbanA.LaaperM.HeckelE.JoyalJ. S.SoleimaniV. D.et al (2020). OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation. Nat. Commun.11, 4116. 10.1038/s41467-020-17885-z

  • CrossRef
  • Google Scholar

• 86

  ShiY.JiaB.XuW.LiW.LiuT.LiuP.et al (2017). Chidamide in relapsed or refractory peripheral T cell lymphoma: A multicenter real-world study in China. J. Hematol. Oncol.10, 69. 10.1186/s13045-017-0439-6

  • CrossRef
  • Google Scholar

• 87

  ShonoT.YokoyamaN.UesakaT.KurodaJ.TakeyaR.YamasakiT.et al (2008). Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival. Int. J. Cancer123, 787–792. 10.1002/ijc.23569

  • CrossRef
  • Google Scholar

• 88

  SilvaL.CoelhoP.SoaresR.PrudêncioC.VieiraM. (2019). Quinoxaline-1, 4-dioxide derivatives inhibitory action in melanoma and brain tumor cells. Future Med. Chem.11, 645–657. 10.4155/fmc-2018-0251

  • CrossRef
  • Google Scholar

• 89

  SingerE.JudkinsJ.SalomonisN.MatlafL.SoteropoulosP.McAllisterS.et al (2015). Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death Dis.6, e1601. 10.1038/cddis.2014.566

  • CrossRef
  • Google Scholar

• 90

  SohalR. S.AllenR. G. (1990). Oxidative stress as a causal factor in differentiation and aging: A unifying hypothesis. Exp. Gerontol.25, 499–522. 10.1016/0531-5565(90)90017-v

  • CrossRef
  • Google Scholar

• 91

  TakabeH.WarnkenZ. N.ZhangY.DavisD. A.SmythH. D. C.KuhnJ. G.et al (2018). A repurposed drug for brain cancer: Enhanced atovaquone amorphous solid dispersion by combining a spontaneously emulsifying component with a polymer carrier. Pharmaceutics10, E60. 10.3390/pharmaceutics10020060

  • CrossRef
  • Google Scholar

• 92

  TanA. C.AshleyD. M.LópezG. Y.MalinzakM.FriedmanH. S.KhasrawM.et al (2020). Management of glioblastoma: State of the art and future directions. Ca. Cancer J. Clin.70, 299–312. 10.3322/caac.21613

  • CrossRef
  • Google Scholar

• 93

  TavanaE.MollazadehH.MohtashamiE.ModaresiS. M. S.HosseiniA.SabriH.et al (2020). Quercetin: A promising phytochemical for the treatment of glioblastoma multiforme. Biofactors46, 356–366. 10.1002/biof.1605

  • CrossRef
  • Google Scholar

• 94

  ThannickalV. J.FanburgB. L. (2000). Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell. Mol. Physiol.279, L1005–L1028. 10.1152/ajplung.2000.279.6.L1005

  • CrossRef
  • Google Scholar

• 95

  TomarM. S.KumarA.SrivastavaC.ShrivastavaA. (2021). Elucidating the mechanisms of Temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim. Biophys. Acta. Rev. Cancer1876, 188616. 10.1016/j.bbcan.2021.188616

  • CrossRef
  • Google Scholar

• 96

  TrachoothamD.AlexandreJ.HuangP. (2009). Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach?Nat. Rev. Drug Discov.8, 579–591. 10.1038/nrd2803

  • CrossRef
  • Google Scholar

• 97

  ValkoM.LeibfritzD.MoncolJ.CroninM. T.MazurM.TelserJ.et al (2007). Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol.39, 44–84. 10.1016/j.biocel.2006.07.001

  • CrossRef
  • Google Scholar

• 98

  ValkoM.RhodesC. J.MoncolJ.IzakovicM.MazurM. (2006). Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact.160, 1–40. 10.1016/j.cbi.2005.12.009

  • CrossRef
  • Google Scholar

• 99

  WadaT.PenningerJ. M. (2004). Mitogen-activated protein kinases in apoptosis regulation. Oncogene23, 2838–2849. 10.1038/sj.onc.1207556

  • CrossRef
  • Google Scholar

• 100

  WangC.HeC.LuS.WangX.WangL.LiangS.et al (2020). Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF. Cell Death Dis.11, 630. 10.1038/s41419-020-02866-3

  • CrossRef
  • Google Scholar

• 101

  WangG. L.SemenzaG. L. (1995). Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem.270, 1230–1237. 10.1074/jbc.270.3.1230

  • CrossRef
  • Google Scholar

• 102

  WangJ.HaoH.YaoL.ZhangX.ZhaoS.LingE. A.et al (2012). Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells. J. Pineal Res.53, 180–187. 10.1111/j.1600-079X.2012.00985.x

  • CrossRef
  • Google Scholar

• 103

  WangK.FuX. T.LiY.HouY. J.YangM. F.SunJ. Y.et al (2016). Induction of S-phase Arrest in human glioma cells by selenocysteine, a natural selenium-containing agent via triggering reactive oxygen species-mediated DNA damage and modulating MAPKs and AKT pathways. Neurochem. Res.41, 1439–1447. 10.1007/s11064-016-1854-8

  • CrossRef
  • Google Scholar

• 104

  WangP. F.CaiH. Q.ZhangC. B.LiY. M.LiuX.WanJ. H.et al (2018). Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas. J. Neuroinflammation15, 145. 10.1186/s12974-018-1187-4

  • CrossRef
  • Google Scholar

• 105

  WangY.YingX.XuH.YanH.LiX.TangH.et al (2017). The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals. Int. J. Nanomedicine12, 1369–1384. 10.2147/IJN.S124276

  • CrossRef
  • Google Scholar

• 106

  WangY.ZhangJ.YangY.LiuQ.XuG.ZhangR.et al (2019). ROS generation and autophagosome accumulation contribute to the DMAMCL-induced inhibition of glioma cell proliferation by regulating the ROS/MAPK signaling pathway and suppressing the Akt/mTOR signaling pathway. Onco. Targets. Ther.12, 1867–1880. 10.2147/OTT.S195329

  • CrossRef
  • Google Scholar

• 107

  WarisG.AhsanH. (2006). Reactive oxygen species: Role in the development of cancer and various chronic conditions. J. Carcinog.5, 14. 10.1186/1477-3163-5-14

  • CrossRef
  • Google Scholar

• 108

  WeiJ.MengL.HouX.QuC.WangB.XinY.et al (2019). Radiation-induced skin reactions: Mechanism and treatment. Cancer Manag. Res.11, 167–177. 10.2147/CMAR.S188655

  • CrossRef
  • Google Scholar

• 109

  WuL.WangF.XuJ.ChenZ. (2019). PTPN2 induced by inflammatory response and oxidative stress contributed to glioma progression. J. Cell. Biochem.120, 19044–19051. 10.1002/jcb.29227

  • CrossRef
  • Google Scholar

• 110

  YangH.ChenW.MaJ.ZhaoJ.LiD.CaoY.et al (2020). Silver nanotriangles and chemotherapeutics synergistically induce apoptosis in glioma cells via a ROS-dependent mitochondrial pathway. Int. J. Nanomedicine15, 7791–7803. 10.2147/IJN.S267120

  • CrossRef
  • Google Scholar

• 111

  YangL.MuY.CuiH.LiangY.SuX. (2017). MiR-9-3p augments apoptosis induced by H2O2 through down regulation of Herpud1 in glioma. PLoS One12, e0174839. 10.1371/journal.pone.0174839

  • CrossRef
  • Google Scholar

• 112

  YangW.XiaY.CaoY.ZhengY.BuW.ZhangL.et al (2012). EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol. Cell48, 771–784. 10.1016/j.molcel.2012.09.028

  • CrossRef
  • Google Scholar

• 113

  YangW.ZhengY.XiaY.JiH.ChenX.GuoF.et al (2012). ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol.14, 1295–1304. 10.1038/ncb2629

  • CrossRef
  • Google Scholar

• 114

  ZhaoP.ZhaoL.ZouP.LuA.LiuN.YanW.et al (2012). Genetic oxidative stress variants and glioma risk in a Chinese population: A hospital-based case-control study. BMC Cancer12, 617. 10.1186/1471-2407-12-617

  • CrossRef
  • Google Scholar

• 115

  ZhengL.WangC.LuoT.LuB.MaH.ZhouZ.et al (2017). JNK activation contributes to oxidative stress-induced parthanatos in glioma cells via increase of intracellular ROS production. Mol. Neurobiol.54, 3492–3505. 10.1007/s12035-016-9926-y

  • CrossRef
  • Google Scholar

• 116

  ZhongH.De MarzoA. M.LaughnerE.LimM.HiltonD. A.ZagzagD.et al (1999). Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res.59, 5830–5835.

  • Google Scholar

• 117

  ZhouH.HanL.WangH.WeiJ.GuoZ.LiZ.et al (2020). Chidamide inhibits glioma cells by increasing oxidative stress via the miRNA-338-5p regulation of hedgehog signaling. Oxid. Med. Cell. Longev.2020, 7126976. 10.1155/2020/7126976

  • CrossRef
  • Google Scholar

• 118

  ZhuJ.WangH.FanY.LinY.ZhangL.JiX.et al (2014). Targeting the NF-E2-related factor 2 pathway: A novel strategy for glioblastoma (review). Oncol. Rep.32, 443–450. 10.3892/or.2014.3259

  • CrossRef
  • Google Scholar