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ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

Anastasiya V. Snezhkina, Anna V. Kudryavtseva, Olga L. Kardymon and 4 more

Oxidative Medicine and Cellular Longevity · 2019 · Review

doi:10.1155/2019/6175804

Abstract

Reactive oxygen species (ROS) are by-products of normal cell activity. They are produced in many cellular compartments and play a major role in signaling pathways. Overproduction of ROS is associated with the development of various human diseases (including cancer, cardiovascular, neurodegenerative, and metabolic disorders), inflammation, and aging. Tumors continuously generate ROS at increased levels that have a dual role in their development. Oxidative stress can promote tumor initiation, progression, and resistance to therapy through DNA damage, leading to the accumulation of mutations and genome instability, as well as reprogramming cell metabolism and signaling. On the contrary, elevated ROS levels can induce tumor cell death. This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Reactive oxygen species (ROS) are formed as natural by-products of normal cell activity and participate in cellular signaling. The increase in ROS levels has harmful effects on cell homeostasis, structures, and functions and results in oxidative stress. As such, the disturbance of cellular redox balance is a risk factor for the development of various pathologies.

Tumor cells are characterized by a high level of ROS. ROS overproduction can result from changes in many processes, such as oxidative phosphorylation (OXPHOS), transition metal ions, oxidase activity, protein folding, thymidine, and polyamine catabolism. ROS can be generated both in various cellular compartments and in the tumor microenvironment.

ROS have a dual role in cancer development; on one hand, they can promote molecular genetic alterations that are necessary for tumor initiation, growth, and progression, as well as acquisition of treatment resistance. On the other hand, permanent elevated ROS levels have cytotoxic effects, inducing activation of apoptotic pathways or inhibiting resistance to anticancer treatments.

In this review, we discuss the main sources of ROS production in animal cells and the antioxidant defense systems that could be implicated in the redox state of cancer cells (to a significant or less significant extent).

2.1. Mitochondria

Mitochondria are a prime source of endogenous ROS due to its main role in oxidative ATP production, in which molecular oxygen (O2) is reduced to water in the electron transport chain. The superoxide radical (O2•−) is produced at a number of sites in the mitochondria, including complex I (sites IQ and IF), complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, Q oxidoreductase, pyruvate dehydrogenase, and 2-oxoglutarate dehydrogenase. All the sites release superoxide radical into the mitochondrial matrix (MM), and two of them, complex III (site IIIQo) and glycerol 3-phosphate dehydrogenase, also generate ROS into the intermembrane mitochondrial space (IMS). Manganese superoxide dismutase (Mn-SOD) converts the superoxide radical to hydrogen peroxide (H2O2) in the MM, while Cu- and Zn-SOD convert the superoxide radical in the IMS or cytosol. The H2O2 in the MM can further be converted by mitochondrial aconitase to a hydroxyl radical (•OH) via a Fenton reaction. One more site of ROS production in the mitochondria is the cytochrome (CYP) catalytic cycle. CYP enzymes metabolize a wide range of organic substrates (lipids, steroid hormones, xenobiotics, and others) to give rise to superoxide radical and H2O2 as by-products. Several CYP family members were shown to be present in the mitochondrial membrane of steroidogenic organs, as well as in the liver and kidney. Furthermore, several other mammalian proteins, such as NADH-cytochrome b5 reductase, dihydroorotate dehydrogenase, complex II (succinate dehydrogenase), and monoamine oxidases (MAO), were shown to generate ROS in the mitochondria.

Mitochondria are protected from ROS by multiple defense systems and antioxidants: glutathione peroxidases (GPXs), thioredoxin peroxidases (TRXPs), superoxide dismutases (SODs), peroxiredoxins (PRDXs), glutathione (GSH), thioredoxin 2 (TRX2), glutaredoxin 2 (GRX2), cytochrome c oxidase (complex IV), coenzyme Q, ascorbic acid, tocopherol, vitamin E, and carotene. Moreover, catalase (CAT), which commonly detoxifies H2O2 in the peroxisome, was found in rat heart mitochondria (but not in other tissues).

Mitochondrion-generated ROS were widely shown to be implicated in various human pathologies, including inflammation, cancer, mitochondrial and neurodegenerative diseases, diabetes, chronic diseases, and aging. Elevated ROS levels and mitochondrial dysfunction, present in many cancers, lead to oxidative damage of cellular structures, in particular, genomic and mitochondrial DNA, somatic mutations, genome instability, activation of oncogenes and inactivation of tumor suppressor genes, and alterations in metabolic and signaling pathways with simultaneous activation of compensatory antioxidant mechanisms, that all contribute to cell transformation. However, overproduction of ROS can also promote tumor cell apoptosis and such strategies have effectively been used for anticancer treatment.

2.2. Transition Metal Ions

One of the major mechanisms of metal carcinogenicity is the ability of transition metal ions to induce oxidative stress. Fenton and Haber-Weiss reactions are frequently responsible for ROS generation in living cells. During these reactions, H2O2 is decomposed with the participation of metal ions, such as iron (Fe), copper (Cu), zinc (Zn), and aluminum (Al), leading to the production of hydroxyl radical (•OH) and hydroxyl anion (OH−). Other carcinogenic metal ions (antimony, arsenic, chromium, cobalt, nickel, and vanadium) were also supposed to be able to generate ROS in cellular redox reactions. The hydroxyl radicals produced can attack the DNA, causing oxidative DNA adduct formation. The adducts 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) are the most predominant, resulting from the addition of hydroxyl radicals to guanine. These compounds are widely considered as markers of endogenous oxidative DNA damage as well as a risk factor for cancer development.

2.3. Peroxisome Activity

Peroxisomes have multiple functions in living cells, including fatty acid β-oxidation and α-oxidation as well as metabolism of purines, polyamines, amino acids, glyoxylate, reactive oxygen and nitrogen species (RNS), transition metal ions, and others. Peroxisomes generate a wide range of ROS and RNS: H2O2, superoxide radical (O2•−), hydroxyl radical (•OH), nitric oxide (NO•), and peroxynitrite (ONOO−).

The peroxisome was first described as an H2O2-producing and H2O2-degrading organelle. Despite the presence of CAT, peroxisomes are one of the main sources of H2O2. H2O2 is released as a by-product during the normal catalytic activity of many peroxisomal enzymes, and it can also be generated by the spontaneous or enzymatic dismutation of the superoxide radical. H2O2 can generate hydroxyl radicals (•OH) via a Fenton reaction.

Peroxisomes produce superoxide radicals (O2•−) in both the matrix and membrane. In the matrix, two enzymes are responsible for O2•− generation, xanthine oxidoreductase (XOR), and urate oxidase (UO). XOR catalyzes the formation of uric acid during purine metabolism that is further converted to allantoin by UO. Both enzymes generate O2•− and H2O2. However, UO expression was not detected in humans and some primates indicating that uric acid is a terminal compound of purine metabolism. The other source of superoxide radicals is an electron transport chain in the peroxisomal membrane. Moreover, XOR also catalyzes the reduction of nitrates and nitrites to nitric oxide (NO•). NO• can also be produced from L-arginine, in a reaction catalyzed by nitric oxide synthase (NOS). The reaction of O2•− with NO• results in a highly reactive compound called peroxynitrite (ONOO−).

Several antioxidant systems regulate ROS levels in peroxisomes and defend cells from oxidative damage. These include a number of enzymes, such as CAT, superoxide dismutases, peroxiredoxins, glutathione S-transferases (GST), and epoxide hydrolase 2 (EPHX2), as well as nonenzymatic low-molecular weight antioxidants, which are reviewed in detail elsewhere.

Changes in redox homeostasis contribute to cancer development and progression. The peroxisome maintains cellular oxidative balance, and dysregulation of its activity is associated with carcinogenesis. Thus, reduced CAT activity leads to ROS generation and oxidative stress resulting in DNA damage and genome instability promoting cancer development. Decreased CAT expression has been shown in hepatocellular carcinoma and colon, lung, kidney, and prostate cancers, as well as in precancer states, such as prostatic intraepithelial neoplasia (PIN) and cervical intraepithelial neoplasia (CIN). In several cases, decreased CAT activity was associated with a reduced number of peroxisomes.

2.4. Endoplasmic Reticulum

The endoplasmic reticulum (ER) has many general cellular functions, such as protein folding, synthesis, transport, and posttranslational modifications, as well as lipid metabolism and calcium storage. Alterations in the folding pathway lead to accumulation of misfolded and unfolded proteins in the ER lumen resulting in ER stress. This disrupts cell homeostasis and initiates the unfolded protein response (UPR). UPR triggers ROS production, and ROS, in turn, can promote ER stress. In tumor cells, the UPR signaling pathway serves as an adaptive to the stress mechanism supporting their survival and propagation. However, if ER stress is prolonged, the UPR triggers tumor cell apoptosis.

Oxidative protein folding gives rise to a highly oxidative environment in the ER lumen. Protein disulfide isomerase (PDI) catalyzes thiol-disulfide exchange reactions, which form a native disulfide bond in proteins. During this process, PDI is oxidized by endoplasmic reticulum oxidoreductin-1 (ERO1), which accepts electrons from a reduced PDI and transfers them to molecular oxygen, thereby generating H2O2. ERO1 also catalyzes the conversion of glutathione (GSH) to glutathione disulfide (GSSG), besides PDI oxidation. Accumulation of both H2O2 and oxidized glutathione causes ER stress. Furthermore, the ratio between GSH and GSSG is an essential marker of the redox status in the ER lumen. Moreover, GSH was proposed as a potential protection mechanism from ER-associated ROS damage. PDI and ERO1 were found to be upregulated in different types of cancer and were implicated in cancer progression and metastasis. PDI and ERO1 overexpression has been found in patients with non-small cell lung cancer (NSCLC) and was significantly associated with shorter overall survival. Expression of several members of the PDI family was upregulated in ovarian and colorectal cancers while ERO1 overexpression was correlated with the progression and metastasis of breast cancer, as well as with poor survival and high recurrence rates in gastric cancer. ERO1 knockout led to the reduced growth of colorectal cancer cells under hypoxic conditions. Elevated ERO1 expression was associated with poor prognosis in cervical cancer. In the same study, ERO1 knockout inhibited tumor growth and migration of cervical cancer cells.

PDI is also involved in H2O2 generation through interconnections with NOX1 and NOX4, which belong to the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein family. In addition, NOX4 occurs in the NOX4-p22phox complex in the ER membrane and is involved in releasing H2O2 in the ER lumen. One more site of ROS generation in the ER is the microsomal monooxygenase (MMO) system. This is a multienzyme system consisting of multiple cytochrome P450 species, NADPH-P450 reductase (NPR), and cytochrome b5. MMO catalyzes the oxygenation of hydrophobic exogenous compounds and some endogenous substrates, resulting in a production of superoxide radicals and H2O2. Increased MMO-derived ROS production and greater rates of microsomal lipid peroxidation were shown to be associated with the activation of cytochrome P450 2E1 (CYP2E1).

2.5. Thymidine Catabolism

Thymidine phosphorylase (TP) is a rate-limiting enzyme in thymidine catabolism that catalyzes the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1-phosphate (DR1P). TP is upregulated in many tumors and plays an important role in angiogenesis, apoptosis evasion, invasion, and metastasis, as well as in chemotherapy response. Recently, Tabata and coauthors have revealed that TP activity increases NADPH levels via the pentose phosphate pathway (PPP) which activates NADPH oxidase-dependent production of ROS in cancer cells. Previously, it was shown that the addition of thymidine to a TP-overexpressing bladder carcinoma cell line induces cellular oxidative stress. The authors proposed another potential mechanism of TP-induced ROS production. This mechanism is based on excess 2dDR1P produced during thymidine phosphorylation that could be further subjected to transition metal-catalyzed oxidation, leading to ROS generation.

2.6. Polyamine Catabolism

The natural polyamines (PAs), putrescine, spermidine, and spermine, are involved in multiple basic cellular functions, including growth, proliferation, differentiation, apoptosis, migration, and protection from stresses. They are involved in protein posttranslational modifications, regulation of ion channels, maintenance of nucleic acid, and protein structure and stability, as well as cell-cell communications. PA content and catabolism are strongly regulated at different levels by key enzymes in the biosynthesis and transport systems. However, dysregulation of PA catabolism is frequently observed in cancer.

In mammals, putrescine is the first polyamine of the PA catabolism. It is synthesized with the participation of ornithine decarboxylase (ODC). Putrescine is further converted to higher polyamines, spermidine and spermine, a reaction catalyzed by spermidine synthase (SPDS) and spermine synthase (SPMS), respectively. S-Adenosylmethionine decarboxylase (AdoMetDC) supplies the aminopropyl groups in these reactions. The activities of ODC and AdoMetDC are considered to be a rate-limiting factors of PA biosynthesis. The other branch of PA catabolism involves the interconversion cycles where spermine is degraded to spermidine and spermidine to putrescine with the generation of toxic-reactive aldehydes and ROS. Spermine oxidase (SMO) catalyzes the conversion of spermine to spermidine, which is accompanied by 3-aminopropanal and H2O2 release. Spermidine and spermine can also be converted to prior polyamines, with the help of spermidine/spermine-N1-acetyltransferase (SSAT) and acetylpolyamine oxidase (APAO/PAOX). N-Acetyl-3-aminopropanaldehyde and H2O2 are produced as by-products of these reactions. Additionally, another degradative enzyme related to PA catabolism is a diamine oxidase (DAO) that oxidizes putrescine to H2O2, ammonia, and 4-aminobutanal. However, as putrescine is present in relatively low amounts in most mammalian tissues, this reaction does not generate significant amounts of ROS.

Increased PA catabolism can lead to an elevated level of ROS and oxidative stress. Overexpression of SMOX and SAT1, which encode the SMO and SSAT enzymes, respectively, was shown to be interconnected with infection, inflammation, and high risk of cancer. Several studies have reported that bacterial cytotoxins upregulate the expression of SMOX. The Helicobacter pylori virulence factor, cytotoxin-associated gene A (CagA) protein, promotes an increase in the SMOX mRNA level and enzyme activity in both human and animal gastric epithelial cells. This results in a significant increase in extra- and intracellular H2O2, leading to DNA damage and apoptosis, which can further contribute to inflammation and carcinogenesis. Using a gerbil model, it was shown that H. pylori infection induces overexpression of SMO and oxidative DNA damage and is associated with a high risk of gastric dysplasia and adenocarcinoma. Furthermore, SMO expression was increased in gastric cancer patients infected with H. pylori. In the same study, it was reported that activation of EGFR and ERBB2 signaling is involved in H. pylori-induced upregulation of SMOX.

Enterotoxigenic Bacteroides fragilis (ETBF) infection results in chronic inflammation and can promote colorectal carcinogenesis. B. fragilis toxin (BFT) has also been reported to increase SMOX expression leading to ROS generation and DNA damage in colonic epithelial cells. A study involving patients with colorectal cancer has revealed that SMOX overexpression could be caused by the activation of the transcription factor C/EBPβ, which is involved in the regulation of inflammation and immunity, rather than the ETBF infection. The association of increased SMOX expression and chronic inflammation was also observed in several precancerous conditions such as prostatic intraepithelial neoplasia (PIN) and chronic hepatitis. Interestingly, drug-induced modulation of polyamine catabolism in hepatic cells results in them undergoing an epithelial-mesenchymal transition- (EMT-) like dedifferentiation, which is not, however, associated with elevated ROS levels. This can indicate that ROS overproduction caused by increased polyamine catabolism together with chronic inflammation could be a precursor event of cancer development, but not tumor progression (with respect to metastasis).

On the contrary, an antioxidant role of polyamines has been proposed. Multiple protection mechanisms from oxidative damage with PA participation were reported: direct ROS scavenging, changes in DNA structure and conformation which reduce the possibility of its interactions with reactive species, formation of chelates with metals at low concentration which prevents ROS generation, particularly hydroxyl radicals, or a combination of these mechanisms. Additionally, PA metabolism was linked to p53-mediated ferroptosis in response to oxidative stress. This mechanism is based on p53-induced SSAT activation, in the presence of high levels of ROS, leading to downstream modulation of the expression of ferroptosis components.

2.7. Oxidase Activity

Diamine oxidase (DAO) is a copper-containing amine oxidase that catalyzes the oxidation of polyamines, such as histamine, putrescine, spermidine, and to a lesser extent spermine. All these reactions generate H2O2. DAO activity in mammals varies and was found to be tissue specific. As such, high DAO activity was found in the placenta, kidneys, lungs, small intestine, and liver. Moreover, elevated DAO activity was found in prostate, breast, ovarian, cervical, and endometrial cancers and a decrease in activity was found in colorectal cancer. Increased plasma/serum DAO activity was detected in patients with endometrial, lung, and thyroid cancers. Moreover, serum/plasma DAO activity has been proposed as an indicator of mucosal injury during chemotherapy and can be used for monitoring anticancer drug toxicity.

Acetylpolyamine oxidase (APAO/PAOX) is related to flavin adenine dinucleotide- (FAD-) containing enzymes and catalyzes the oxidation of both spermidine and spermine in peroxisomes. Depending on the substrate, N1-acetylspermine or N1-acetylspermidine, APAO produces spermidine or putrescine, respectively, generating H2O2 as a by-product. The presence of starting substrates of APAO is controlled by SSAT activity. Induction of the SSAT/APAO pathway can increase oxidative stress; however, it seems to have a more significant contribution than the one-step spermine oxidation reaction catalyzed by SMO.

Spermine oxidase (SMO) is a FAD-dependent oxidase that acts directly on spermine generating spermidine, H2O2, and 3-aminopropanal. Unlike APAO, SMO is not a peroxisomal enzyme and is located in cytoplasm or nucleus. SMO activity can produce higher levels of oxidative cellular damage. Elevated expression of SMOX was shown in prostate and colorectal cancers. Furthermore, SMOX overexpression followed by downstream oxidative damage, chronic inflammation, and carcinogenesis is often induced by infections (discussed above).

Xanthine oxidoreductase (XOR) is a molybdenum iron-sulfur flavin hydroxylase that exists in two forms, xanthine dehydrogenase (XDH) and xanthine oxidase (XOD). XDH can be converted to XOD either irreversibly by proteolysis or reversibly by modification of cysteine residues. The enzyme catalyzes the oxidation of hypoxanthine to xanthine or xanthine to uric acid during purine metabolism. Both XDH and XOD generate H2O2 and O2•− through NADH oxidation. Nevertheless, for XDH, NAD+ is a more preferable substrate compared to oxygen, and therefore, it cannot directly produce ROS. XOR-released superoxide radicals rapidly react with nitric oxide (NO•) generating peroxynitrite (ONOO−). NO•, in turn, is produced by NOS activity or even by XOR under hypoxic conditions. The association of XOR with neoplastic transformation was first reported many years ago. Decreased XOR activity was frequently found in many animal and human tumors. XOR activity was increased in meningioma, astrocytoma, and laryngeal and colorectal cancers. This indicates that dysregulation of purine metabolism and ROS levels can play a role in tumor pathogenesis.

Cytochrome P450 (CYP) oxidase is part of the microsomal electron transport system. It belongs to the CYP superfamily of integral membrane proteins that catalyze the oxidation of numerous organic substrates, accompanied by the reduction of molecular oxygen. CYP enzymes also have peroxygenase and peroxidase activity, using H2O2 either for direct oxidation of substrates or as a donor of oxygen atoms. The prosthetic heme group in CYP enzymes is essential for their activity. H2O2 and superoxide radicals are produced during the CYP monooxygenase cycle; the former can be further decomposed to hydroxyl radicals (•OH) in the presence of ferrous iron via a Fenton reaction. CYP enzymes are predominantly located in the endoplasmic reticulum and mitochondria and are expressed in many mammalian tissues. CYP-related ROS generation depends on CYP isoforms, content and type of substrates, pH, ionic strength, the action of cytochrome b5, oxygen concentration, oligomerization, and so on. Studies have shown that CYP2E1 induces higher ROS production than other CYP enzymes and that its activation or overexpression leads to increased ROS levels. CYP enzyme activity can promote carcinogenesis through increased ROS production. As such, overexpression of CYP family genes was observed in many cancers.

The NADPH oxidase (NOX) family includes seven members: NOX1, NOX2, NOX3, NOX4, NOX5, dual oxidase 1 (DUOX1), and DUOX2. These are transmembrane proteins that transfer an electron from the NADPH substrate to FAD across biological membranes in order to reduce oxygen to a superoxide radical. Dysregulation of NOX activity leads to elevated ROS production that can contribute to tumorigenesis, cell transformation, tumor growth, angiogenesis, and metastasis. NOX-derived ROS were shown to be implicated in many common cancer types (e.g., bladder, colorectal, breast, kidney, lung, and prostate cancers), as well as acute myeloid leukemia and non-Hodgkin's lymphoma. Moreover, NOX family members are involved in host defense and innate immunity. NOX could be activated by various infectious agents resulting in increased ROS production which promotes the death of the infected cells as well as an inflammatory response. Toll-like receptors (TLRs) located at the plasma membrane recognize conserved structures of bacteria, viruses, or fungi and trigger downstream signaling. TLRs interact with NOX, leading to increased ROS generation, as well as subsequent activation of the transcription factor NF-κB, and production of cytokines and chemokines. Nucleotide-binding oligomerization domain- (NOD-) like receptors (NLRs) can also recognize components of the bacterial cell wall and other bacterial molecules (e.g., RNA, toxins, and ligands). NLR family members, NACHT lectin-like receptor and PYD domain-containing proteins (NLRPs), promote the assembly of inflammasomes and mediate the activation of inflammatory caspases. ROS were shown to be required for the activation of NLRP3-mediated inflammasomes, and NOX, as one of the main sources of ROS production, can be involved in NLR signaling. The important role of NOX-produced ROS in the NLR system was also reported by Lipinski et al.. Additionally, hepatitis C virus (HCV) infection can induce NOX1 and NOX4 expression, leading to increased ROS generation in hepatocytes. It was shown that HCV modulates NOX4 through TGF-beta. Moreover, HCV can induce immune dysfunction via HCV nonstructural protein 3- (NS3-) induced release of ROS from phagocytes, resulting in the apoptosis of T lymphocytes, natural killer (NK) cells, and NKT cells.

Cyclooxygenases (COX) and lipoxygenases (LOX) participate in polyunsaturated fatty acid (PUFA) metabolism, by producing bioactive eicosanoids. COX and LOX oxygenate arachidonic acid resulting in the formation of prostaglandin G2 and H2 (PGG2/PGH2) and fatty acid hydroperoxide, respectively, a reaction that is accompanied by ROS release. Peroxyl radicals (ROO•) and alkoxyl radicals (RO•) are intermediates of the hydroperoxide metabolism. Moreover, the arachidonic acid pathway itself could be responsible for ROS generation via NADPH oxidase activation. In spite of the similarity between COX/LOX-catalyzing reactions, they have a completely different sequence, structure, cellular localization, and tissue expression. COX is present in three isoforms - constitutive (COX-1), inducible (COX-2), and splice variant of COX-1 (COX-3). The PTGS1 gene encodes for both COX-1 and COX-3 isoenzymes; however, COX-3 activity in humans remains unclear. PTGS2 encodes for COX-2. COX-1 predominantly regulates basal prostaglandin metabolism and normal tissue homeostasis. COX-2 is induced by proinflammatory stimuli, cytokines, and growth factors in response to inflammation, tissue injury, and tumorigenesis. COX-2 overexpression and increased prostaglandin biosynthesis have been found in both the precancer stages and various tumors. COX1 was upregulated in breast, cervical, ovarian, endometrial, and colorectal cancers, as well as in cholangiocarcinoma.

LOX constitutes a large family of nonheme iron-containing dioxygenases; five LOX isoenzymes were found in humans (5-LOX, 12-LOX, 12R-LOX, two 15-LOX, and 3-LOX/E-LOX). Dysregulated LOX expression was observed in various tumors and animal models. A dual role of LOX in tumorigenesis has been proposed, as they can be involved in both neoplastic transformation and tumor suppression.

Monoamine oxidases A and B (MAOA and MAOB) are mitochondrial FAD-dependent enzymes encoded by separate genes. They catalyze the oxidative deamination of monoamines, including monoamine neurotransmitters (e.g., norepinephrine, dopamine, serotonin, and epinephrine), exogenous dietary amines, and drugs, generating H2O2 and aldehydes as by-products. Excessive MAO activity leads to enhanced ROS production and mitochondrial damage and is implicated in aging, cardiovascular diseases, neurodegenerative disorders, and cancer. Increased MAOA expression was found in lung, prostate, and breast cancers, as well as hepatocellular carcinoma and cholangiocarcinoma. Moreover, several studies suggested that MAOA can promote cancer progression through induction of EMT. Conversely, MAOA was downregulated in a number of cancer tissues and significantly differed between them. In this case, the potential mechanism of tumor progression can be related to an increase in the amounts of MAOA substrate epinephrine.

Lysyl oxidase is a family of copper-dependent enzymes that play a primary role in the remodeling of the extracellular matrix (ECM). They catalyze the conversion of specific lysine residues into reactive aldehyde groups in collagen and elastin, forming protein crosslinks. The lysyl oxidase catalytic cycle also produces H2O2, which can increase oxidative stress thereby promoting carcinogenesis. Overexpression of lysyl oxidase and its involvement in tumor progression and metastasis were shown in various cancers.

2.8. Signaling Pathways

The PI3K/AKT/PTEN signaling pathway is implicated in NOX-derived ROS production. PTEN (phosphatase and tensin homolog) is a tumor suppressor responsible for the negative regulation of PI3K/AKT signaling. Loss of PTEN expression or mutations in the gene, as well as dysregulation of the PI3K/AKT signaling pathway, were frequently found in many tumors.

NOXs are multimeric enzymes consisting of several proteins that are distributed between the membrane and cytosol when inactive. Upon activation by different stimuli, the cytosolic subunits interact with integral membrane subunits, forming the functional NOX enzymes which can generate ROS. It was shown that PI3K/AKT inhibitors can reduce NOX-dependent ROS generation through the inhibition of NOX subunit translocation into the membrane. In addition, membrane depolarization with downstream PI3K/AKT and (protein kinase C) PKC activation causes NOX assembly and ROS production. Moreover, oxidative stress inhibits PTEN-induced PI3K/AKT signaling, which promotes both the expression of cell survival genes and ROS production. Such mechanisms may contribute to tumor cell proliferation and growth under oxidative conditions. Several other enzymes, including PKC, mitogen-activated protein kinases (MAPK), cAMP-dependent protein kinases (PKA), p21-activated kinases (PAK), and PKB/AKT, can modulate the activation of NOXs through phosphorylation of their cytosolic subunits, thereby increasing the level of ROS. All the aforementioned enzymes were shown to be greatly involved in cancer development.

Transcription factor p53 is a widely known tumor suppressor, involved in regulating the expression of various genes encoding for both ROS-producing and antioxidant-related components. p53 induces the expression of glutathione peroxidase 1 ( GPX1) and mitochondrial superoxide dismutase 2, both components of the key antioxidant defense system. Moreover, p53 regulates the expression of sestrins (SESN1 and SESN2) that are required for peroxiredoxins regeneration. Phosphate-activated mitochondrial glutaminase (GLS2) converts glutamine to glutamate, which is a precursor for glutathione synthesis. GLS2 expression can be induced by p53 in response to DNA damage or oxidative stress to promote antioxidant defense by controlling the GSH/GSSG ratio. Other p53-inducible antioxidant genes are TIGAR and ALDH4. TIGAR negatively regulates glycolysis and decreases intracellular ROS levels, while aldehyde dehydrogenase 4 (ALDH4) is a NAD+-dependent enzyme that catalyzes the second step of the proline degradation pathway in the mitochondrial matrix. Overexpression of ALDH4 in p53-null cells inhibits ROS generation and apoptosis.

The function of prooxidant p53 is based on its ability to regulate the expression of genes encoding for prooxidant enzymes, such as PUMA (the p53-upregulated modulator of apoptosis), p66Shc (66 kDa Src collagen homologue (Shc) adaptor protein), and other proteins encoded by a group of p53-induced genes (PIGs). PUMA overexpression induces BCL2-associated X (BAX) protein-dependent ROS generation (predominantly superoxide radicals and H2O2) and apoptosis in colorectal cancer cells. p66Shc generates mitochondrial H2O2 as signaling molecules for the induction of apoptosis. PIG is a family of proteins, whose several members were shown to influence the cell redox status. P53-induced activation of PIGs results in increased ROS levels and mitochondria-derived apoptosis in colorectal cancer cells. It was shown that p53 promotes the expression of PIG3, BAX, and PUMA leading to an increase in intracellular ROS levels and induction of apoptosis. Moreover, the authors have demonstrated that p53 induction is associated with the excessive ROS release by mitochondria, which supports its prooxidant role.

3. Role of Glycolysis and the Pentose Phosphate Pathway in Antioxidant Defense

Glycolysis and the pentose phosphate pathway are involved in ROS detoxification. Glycolysis occurs in living cells both in anaerobic and aerobic conditions. Aerobic glycolysis generates pyruvate that is converted to acetyl-CoA with the release of carbon dioxide in the mitochondrial tricarboxylic acid (TCA) cycle, while in the absence of oxygen, lactate is produced. Most tumor cells use anaerobic glycolysis even in the presence of oxygen; this phenomenon is termed the “Warburg effect”. Glycolysis reprogramming allows tumor cells to redirect this process to support de novo nucleotide synthesis during proliferation. Dysregulation in the expression of genes encoding for key glycolytic components has been found in many tumors. Increased glycolysis in tumor cells can reduce ROS production via a decrease in OXPHOS activity.

The NADPH/NADP+ ratio is important for antioxidant defense; NADPH acts as a donor of reductive potential to glutathione and thioredoxin reductases. The main source of NADPH is the oxidative branch of the pentose phosphate pathway (ox-PPP). Glucose-6-phosphate (G6P) derived from glucose phosphorylation by hexokinases (HKs) is reduced to 6-phosphogluconate and NADPH via glucose-6-phosphate dehydrogenase (G6PD) during the first step of ox-PPP. In the next step, 6-phosphogluconate dehydrogenase (6PG) catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose-5-phosphate (Ru5P) providing the additional NADPH. The NADP+/NADPH ratio regulates G6PD and 6PG activity in order to produce more NADPH for oxidative stress prevention. Several glycolytic enzymes, such as phosphofructokinase-1 (PFK1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and pyruvate kinase (PK), as well as the TP53-inducible glycolysis and apoptosis regulator (TIGAR), are involved in the redirection of glycolytic flux through the ox-PPP in order to reduce the ROS level. Moreover, the acceleration of glycolysis and PPP in a tumor cell can protect it from oxidative damage.

4. Tumor Microenvironment

Solid tumors are commonly infiltrated with different types of cells, including cancer-associated fibroblasts (CAFs), immune cells, pericytes, adipocytes, and other tissue-associated cells. This forms a distinct tumor microenvironment that comprises cell-cell and cell-extracellular matrix interactions, as well as many soluble factors. The latter include vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), angiopoietins (ANGs), transforming growth factors (TNFs), ROS, chemokines, cytokines, exosomes, microRNAs, Ca2+, K+, Na+, H+, and other ions. The tumor microenvironment plays an essential role in tumor initiation, progression, and metastasis. It is also involved in the resistance to targeted therapy, radiation, and chemotherapy, as well as sensitivity to immunotherapy.

Relatively stable ROS, such as H2O2, which is produced at a high level by tumor cells, can diffuse into the extracellular space. H2O2 can freely cross membranes; however, the cells seem to regulate H2O2 transport by changes in membrane lipid composition, thereby maintaining cellular H2O2 concentration. Aquaporins (AQPs) have also been found to be transporters of H2O2. Moreover, superoxide dismutase 3 (SOD3, EC-SOD) and NADPH oxidase provide extracellular ROS sources. SOD3, which is located in the extracellular space, catalyzes the dismutation of the superoxide anion into H2O2, while several NOX isoforms generate H2O2 and O2•− outside cells. Extracellular ROS signaling in tumor cells with the participation of SOD and NOX enzymes has been well described by Bauer et al.. Briefly, NOX located in the plasma membrane produces O2•− into the extracellular space. The superoxide radical, in turn, dismutates to H2O2 during the hypochlorous acid (HOCl) pathway. Peroxidases (POD) use the H2O2 as a substrate to generate HOCl, which further reacts with hydroxyl anions (OH−) leading to the formation of hydroxyl radicals (•OH). NOX-generated O2•− is reduced to H2O2 either by SOD3 or spontaneously; membrane CAT decomposes the produced H2O2 thereby inhibiting HOCl signaling. CAT can also decompose peroxynitrite (ONOO−) derived from the reaction between NO and H2O2 that prevents hydroxyl radical formation through the NO/peroxynitrite pathway.

Apart from tumor cells, cancer-associated fibroblasts also release extracellular H2O2 that induces oxidative stress in normal fibroblasts, triggering their reprogramming to CAFs and promoting field cancerization, epithelial cell transformation and growth, and cancer aggressiveness. Immune cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), neutrophils, eosinophils, and mononuclear phagocytes, can also generate ROS (mainly H2O2) into the tumor microenvironment.

The major mechanisms of ROS generation and detoxification are presented in Table 1 and Figure 1.

5. Conclusions

ROS are generated by multiple cellular processes and can be overproduced in response to different stimuli. Normal cells can maintain oxidative homeostasis owing to the activity of various antioxidant systems which control ROS production through changes in metabolic and signaling pathways. Upon a permanent increase in ROS levels, the antioxidant defense mechanisms can promote cell death. However, oxidative stress damages many molecules, cell structures, and functions leading to the development of pathological states, such as inflammation, aging, neurodegenerative disorders, and cancer. ROS are greatly implicated in tumorigenesis, and summarizing the current data on ROS biology is important for understanding the mechanisms of tumor initiation, promotion, and progression, as well as for treatment development.

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    Not in our library10.1073/pnas.1010203108

  104. 104.

    Snezhkina A. V., Krasnov G. S., Lipatova A. V., et al. The dysregulation of polyamine metabolism in colorectal cancer is associated with overexpression of c-Myc and C/EBPβ rather than enterotoxigenic Bacteroides fragilis infection. Oxidative Medicine and Cellular Longevity. 2016;2016:11.

    Not in our library10.1155/2016/2353560

  105. 105.

    Goodwin A. C., Jadallah S., Toubaji A., et al. Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues. The Prostate. 2008;68(7):766-772.

    Not in our library10.1002/pros.20735

  106. 106.

    Smirnova O. A., Keinanen T. A., Ivanova O. N., et al. Hepatitis C virus alters metabolism of biogenic polyamines by affecting expression of key enzymes of their metabolism. Biochemical and Biophysical Research Communications. 2017;483(2):904-909.

    Not in our library10.1016/j.bbrc.2017.01.032

  107. 107.

    Hu T., Sun D., Zhang J., et al. Spermine oxidase is upregulated and promotes tumor growth in hepatocellular carcinoma. Hepatology Research. 2018;48(12):967-977.

    Not in our library10.1111/hepr.13206

  108. 108.

    Ivanova O. N., Snezhkina A. V., Krasnov G. S., et al. Activation of polyamine catabolism by N1,N11-diethylnorspermine in hepatic HepaRG cells induces dedifferentiation and mesenchymal-like phenotype. Cells. 2018;7(12):p. 275.

    Not in our library10.3390/cells7120275

  109. 109.

    Spotheim-Maurizot M., Ruiz S., Sabattier R., Charlier M. Radioprotection of DNA by polyamines. International Journal of Radiation Biology. 1995;68(5):571-577.

    Not in our library10.1080/09553009514551561

  110. 110.

    Ha H. C., Sirisoma N. S., Kuppusamy P., Zweier J. L., Woster P. M., Casero R. A. The natural polyamine spermine functions directly as a free radical scavenger. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(19):11140-11145.

    Not in our library10.1073/pnas.95.19.11140

  111. 111.

    Warters R. L., Newton G. L., Olive P. L., Fahey R. C. Radioprotection of human cell nuclear DNA by polyamines: radiosensitivity of chromatin is influenced by tightly bound spermine. Radiation Research. 1999;151(3):354-362.

    Not in our library10.2307/3579948

  112. 112.

    Douki T., Bretonniere Y., Cadet J. Protection against radiation-induced degradation of DNA bases by polyamines. Radiation Research. 2000;153(1):29-35.

    Not in our library10.1667/0033-7587(2000)153[0029:parido]2.0.co;2

  113. 113.

    Feuerstein B. G., Pattabiraman N., Marton L. J. Spermine-DNA interactions: a theoretical study. Proceedings of the National Academy of Sciences of the United States of America. 1986;83(16):5948-5952.

    Not in our library10.1073/pnas.83.16.5948

  114. 114.

    Basu H. S., Schwietert H. C. A., Feuerstein B. G., Marton L. J. Effects of variation in the structure of spermine on the association with DNA and the induction of DNA conformational changes. Biochemical Journal. 1990;269(2):329-334.

    Not in our library10.1042/bj2690329

  115. 115.

    Pedreno E., Lopez-Contreras A. J., Cremades A., Penafiel R. Protecting or promoting effects of spermine on DNA strand breakage induced by iron or copper ions as a function of metal concentration. Journal of Inorganic Biochemistry. 2005;99(10):2074-2080.

    Not in our library10.1016/j.jinorgbio.2005.07.005

  116. 116.

    Ou Y., Wang S. J., Li D., Chu B., Gu W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(44):E6806-E6812.

    Not in our library10.1073/pnas.1607152113

  117. 117.

    Seiler N. Catabolism of polyamines. Amino Acids. 2004;26(3):217-233.

    Not in our library10.1007/s00726-004-0070-z

  118. 118.

    Bieganski T., Kusche J., Lorenz W., Hesterberg R., Stahlknecht C. D., Feussner K. D. Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism. Biochimica et Biophysica Acta (BBA) - General Subjects. 1983;756(2):196-203.

    Not in our library10.1016/0304-4165(83)90092-2

  119. 119.

    Houen G. Mammalian Cu-containing amine oxidases (CAOs): new methods of analysis, structural relationships, and possible functions. APMIS. 1999;107(S96):5-46.

    Not in our library10.1111/apm.1999.107.s96.5

  120. 120.

    Keskinege A., Elgün S., Yilmaz E. Possible implications of arginase and diamine oxidase in prostatic carcinoma. Cancer Detection and Prevention. 2001;25(1):76-79.

    Not in our library

  121. 121.

    Lu J. Y., Yang Y., Liang Y. J. Immunohistochemical study on diamine oxidase in mammary cancer and adenosis. Zhonghua Zhong Liu Za Zhi [Chinese journal of oncology]. 1994;16(4):288-290.

    Not in our library

  122. 122.

    Chanda R., Ganguly A. K. Diamine-oxidase activity and tissue di- and poly-amine contents of human ovarian, cervical and endometrial carcinoma. Cancer Letters. 1995;89(1-2):23-28.

    Not in our library10.1016/0304-3835(94)03648-3

  123. 123.

    Linsalata M., Russo F., Cavallini A., Berloco P., Di Leo A. Polyamines, diamine oxidase, and ornithine decarboxylase activity in colorectal cancer and in normal surrounding mucosa. Diseases of the Colon and Rectum. 1993;36(7):662-667.

    Not in our library10.1007/bf02238593

  124. 124.

    Borglin N. E., Willert B. Increased histaminolytic power of plasma in endometrial adenocarcinoma. Cancer. 1962;15(2):271-275.

    Not in our library10.1002/1097-0142(196203/04)15:2<271::aid-cncr2820150210>3.0.co;2-y

  125. 125.

    Baylin S. B., Abeloff M. D., Wieman K. C., Tomford J. W., Ettinger D. S. Elevated histaminase (diamine oxidase) activity in small-cell carcinoma of the lung. The New England Journal of Medicine. 1975;293(25):1286-1290.

    Not in our library10.1056/nejm197512182932504

  126. 126.

    Andersson A. C., Henningsson S., Jarhult J. Diamine oxidase activity and γ-aminobutyric acid formation in medullary carcinoma of the thyroid. Agents and Actions. 1980;10(4):299-301.

    Not in our library10.1007/bf01971428

  127. 127.

    Namikawa T., Fukudome I., Kitagawa H., Okabayashi T., Kobayashi M., Hanazaki K. Plasma diamine oxidase activity is a useful biomarker for evaluating gastrointestinal tract toxicities during chemotherapy with oral fluorouracil anti-cancer drugs in patients with gastric cancer. Oncology. 2012;82(3):147-152.

    Not in our library10.1159/000336799

  128. 128.

    Tsujikawa T., Uda K., Ihara T., et al. Changes in serum diamine oxidase activity during chemotherapy in patients with hematological malignancies. Cancer Letters. 1999;147(1-2):195-198.

    Not in our library10.1016/s0304-3835(99)00307-9

  129. 129.

    Holtta E. Oxidation of spermidine and spermine in rat liver: purification and properties of polyamine oxidase. Biochemistry. 1977;16(1):91-100.

    Not in our library10.1021/bi00620a015

  130. 130.

    Pegg A. E. Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator. American Journal of Physiology-Endocrinology and Metabolism. 2008;294(6):E995-1010.

    Not in our library10.1152/ajpendo.90217.2008

  131. 131.

    Wang Y., Casero R. A. Mammalian polyamine catabolism: a therapeutic target, a pathological problem, or both? Journal of Biochemistry. 2006;139(1):17-25.

    Not in our library10.1093/jb/mvj021

  132. 132.

    Wang Y., Devereux W., Woster P. M., Stewart T. M., Hacker A., Casero R. A. Cloning and characterization of a human polyamine oxidase that is inducible by polyamine analogue exposure. Cancer Research. 2001;61(14):5370-5373.

    Not in our library

  133. 133.

    Vujcic S., Diegelman P., Bacchi C. J., Kramer D. L., Porter C. W. Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. Biochemical Journal. 2002;367(3):665-675.

    Not in our library10.1042/bj20020720

  134. 134.

    Murray-Stewart T., Wang Y., Goodwin A., Hacker A., Meeker A., Casero R. A. Nuclear localization of human spermine oxidase isoforms - possible implications in drug response and disease etiology. The FEBS Journal. 2008;275(11):2795-2806.

    Not in our library10.1111/j.1742-4658.2008.06419.x

  135. 135.

    Pledgie A., Huang Y., Hacker A., et al. Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. Journal of Biological Chemistry. 2005;280(48):39843-39851.

    Not in our library10.1074/jbc.m508177200

  136. 136.

    Stirpe F., Della Corte E. The regulation of rat liver xanthine oxidase. Conversion in vitro of the enzyme activity from dehydrogenase (type D) to oxidase (type O). Journal of Biological Chemistry. 1969;244(14):3855-3863.

    Not in our library

  137. 137.

    Nishino T., Nishino T. The conversion from the dehydrogenase type to the oxidase type of rat liver xanthine dehydrogenase by modification of cysteine residues with fluorodinitrobenzene. Journal of Biological Chemistry. 1997;272(47):29859-29864.

    Not in our library10.1074/jbc.272.47.29859

  138. 138.

    Nishino T., Okamoto K., Eger B. T., Pai E. F., Nishino T. Mammalian xanthine oxidoreductase - mechanism of transition from xanthine dehydrogenase to xanthine oxidase. The FEBS Journal. 2008;275(13):3278-3289.

    Not in our library10.1111/j.1742-4658.2008.06489.x

  139. 139.

    Zhang Z., Blake D. R., Stevens C. R., et al. A reappraisal of xanthine dehydrogenase and oxidase in hypoxic reperfusion injury: the role of NADH as an electron donor. Free Radical Research. 1998;28(2):151-164.

    Not in our library10.3109/10715769809065801

  140. 140.

    Harris C. M., Massey V. The oxidative half-reaction of xanthine dehydrogenase with NAD; reaction kinetics and steady-state mechanism. Journal of Biological Chemistry. 1997;272(45):28335-28341.

    Not in our library10.1074/jbc.272.45.28335

  141. 141.

    Millar T. M., Stevens C. R., Benjamin N., Eisenthal R., Harrison R., Blake D. R. Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Letters. 1998;427(2):225-228.

    Not in our library10.1016/s0014-5793(98)00430-x

  142. 142.

    Boyland E., Boyland M. E. Studies in tissue metabolism: lactic dehydrogenase, xanthine oxidase and nucleosidase in tumour and muscle extracts. Biochemical Journal. 1935;29(5):1097-1101.

    Not in our library10.1042/bj0291097

  143. 143.
    Xanthine oxidoreductase in cancer: more than a differentiation marker · 2015
    No notice
  144. 144.

    Kokoglu E., Belce A., Ozyurt E., Tepeler Z. Xanthine oxidase levels in human brain tumors. Cancer Letters. 1990;50(3):179-181.

    Not in our library10.1016/0304-3835(90)90262-v

  145. 145.

    Durak İ., Işik C. Ü., Canbolat O., Akyol Ö., Kavutçu M. Adenosine deaminase, 5′ nucleotidase, xanthine oxidase, superoxide dismutase, and catalase activities in cancerous and noncancerous human laryngeal tissues. Free Radical Biology & Medicine. 1993;15(6):681-684.

    Not in our library10.1016/0891-5849(93)90174-s

  146. 146.

    Oztürk H. S., Karaayvaz M., Kacmaz M., Kavutcu M., Akgül H., Durak I. Activities of the enzymes participating in purine and free-radical metabolism in cancerous human colorectal tissues. Cancer Biochemistry Biophysics. 1998;16(1-2):157-168.

    Not in our library

  147. 147.

    Nebert D. W., Russell D. W. Clinical importance of the cytochromes P450. The Lancet. 2002;360(9340):1155-1162.

    Not in our library10.1016/s0140-6736(02)11203-7

  148. 148.

    Hrycay E. G., Bandiera S. M. Monooxygenase, peroxidase and peroxygenase properties and reaction mechanisms of cytochrome P450 enzymes. Advances in Experimental Medicine and Biology. 2015;851:1-61.

    Not in our library10.1007/978-3-319-16009-2_1

  149. 149.

    Werck-Reichhart D., Feyereisen R. Cytochromes P450: a success story. Genome Biology. 2000;1(6, article reviews3003.1).

    Not in our library10.1186/gb-2000-1-6-reviews3003

  150. 150.

    Hrycay E. G., Bandiera S. M. Involvement of cytochrome P450 in reactive oxygen species formation and cancer. Advances in Pharmacology. 2015;74:35-84.

    Not in our library10.1016/bs.apha.2015.03.003

  151. 151.

    Seliskar M., Rozman D. Mammalian cytochromes P450—importance of tissue specificity. Biochimica et Biophysica Acta (BBA) - General Subjects. 2007;1770(3):458-466.

    Not in our library10.1016/j.bbagen.2006.09.016

  152. 152.

    Bae Y. S., Oh H., Rhee S. G., Yoo Y. D. Regulation of reactive oxygen species generation in cell signaling. Molecules and Cells. 2011;32(6):491-509.

    Not in our library10.1007/s10059-011-0276-3

  153. 153.

    Zangar R. C., Davydov D. R., Verma S. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicology and Applied Pharmacology. 2004;199(3):316-331.

    Not in our library10.1016/j.taap.2004.01.018

  154. 154.

    Caro A. A., Cederbaum A. I. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annual Review of Pharmacology and Toxicology. 2004;44(1):27-42.

    Not in our library10.1146/annurev.pharmtox.44.101802.121704

  155. 155.

    Landry W. D., Cotter T. G. ROS signalling, NADPH oxidases and cancer. Biochemical Society Transactions. 2014;42(4):934-938.

    Not in our library10.1042/bst20140060

  156. 156.

    Bedard K., Krause K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological Reviews. 2007;87(1):245-313.

    Not in our library10.1152/physrev.00044.2005

  157. 157.

    Block K., Gorin Y. Aiding and abetting roles of NOX oxidases in cellular transformation. Nature Reviews Cancer. 2012;12(9):627-637.

    Not in our library10.1038/nrc3339

  158. 158.

    Moloney J. N., Stanicka J., Cotter T. G. Subcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22phox-derived reactive oxygen species in acute myeloid leukemia. Leukemia Research. 2017;52:34-42.

    Not in our library10.1016/j.leukres.2016.11.006

  159. 159.

    Tang C. T., Lin X. L., Wu S., et al. NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. Cellular Signalling. 2018;46:52-63.

    Not in our library10.1016/j.cellsig.2018.02.007

  160. 160.

    Castaldo S. A., da Silva A. P., Matos A., et al. The role of CYBA (p22phox) and catalase genetic polymorphisms and their possible epistatic interaction in cervical cancer. Tumour Biology. 2015;36(2):909-914.

    Not in our library10.1007/s13277-014-2714-2

  161. 161.

    Eun H. S., Cho S. Y., Joo J. S., et al. Gene expression of NOX family members and their clinical significance in hepatocellular carcinoma. Scientific Reports. 2017;7(1):p. 11060.

    Not in our library10.1038/s41598-017-11280-3

  162. 162.

    Panday A., Sahoo M. K., Osorio D., Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cellular & Molecular Immunology. 2015;12(1):5-23.

    Not in our library10.1038/cmi.2014.89

  163. 163.

    Park H. S., Jung H. Y., Park E. Y., Kim J., Lee W. J., Bae Y. S. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-κB. The Journal of Immunology. 2004;173(6):3589-3593.

    Not in our library10.4049/jimmunol.173.6.3589

  164. 164.

    Joo J. H., Ryu J. H., Kim C. H., et al. Dual oxidase 2 is essential for the Toll-like receptor 5-mediated inflammatory response in airway mucosa. Antioxidants & Redox Signaling. 2012;16(1):57-70.

    Not in our library10.1089/ars.2011.3898

  165. 165.

    Yang C. S., Shin D. M., Kim K. H., et al. NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. The Journal of Immunology. 2009;182(6):3696-3705.

    Not in our library10.4049/jimmunol.0802217

  166. 166.

    Martinon F., Tschopp J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death & Differentiation. 2007;14(1):10-22.

    Not in our library10.1038/sj.cdd.4402038

  167. 167.

    Bauernfeind F., Bartok E., Rieger A., Franchi L., Nunez G., Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. The Journal of Immunology. 2011;187(2):613-617.

    Not in our library10.4049/jimmunol.1100613

  168. 168.

    Lipinski S., Till A., Sina C., et al. DUOX2-derived reactive oxygen species are effectors of NOD2-mediated antibacterial responses. Journal of Cell Science. 2009;122(19):3522-3530.

    Not in our library10.1242/jcs.050690

  169. 169.

    de Mochel N. S. R., Seronello S., Wang S. H., et al. Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology. 2010;52(1):47-59.

    Not in our library10.1002/hep.23671

  170. 170.

    Boudreau H. E., Emerson S. U., Korzeniowska A., Jendrysik M. A., Leto T. L. Hepatitis C virus (HCV) proteins induce NADPH oxidase 4 expression in a transforming growth factor β-dependent manner: a new contributor to HCV-induced oxidative stress. Journal of Virology. 2009;83(24):12934-12946.

    Not in our library10.1128/jvi.01059-09

  171. 171.

    Bureau C., Bernad J., Chaouche N., et al. Nonstructural 3 protein of hepatitis C virus triggers an oxidative burst in human monocytes via activation of NADPH oxidase. Journal of Biological Chemistry. 2001;276(25):23077-23083.

    Not in our library10.1074/jbc.m100698200

  172. 172.

    Thoren F., Romero A., Lindh M., Dahlgren C., Hellstrand K. A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. Journal of Leukocyte Biology. 2004;76(6):1180-1186.

    Not in our library10.1189/jlb.0704387

  173. 173.

    Fürstenberger G., Krieg P., Müller-Decker K., Habenicht A. J. R. What are cyclooxygenases and lipoxygenases doing in the driver’s seat of carcinogenesis? International Journal of Cancer. 2006;119(10):2247-2254.

    Not in our library10.1002/ijc.22153

  174. 174.

    Kim C.-M., Kim J.-Y., Kim J.-H. Cytosolic phospholipase A2, lipoxygenase metabolites, and reactive oxygen species. BMB Reports. 2008;41(8):555-559.

    Not in our library10.5483/bmbrep.2008.41.8.555

  175. 175.

    Schneider C., Pratt D. A., Porter N. A., Brash A. R. Control of oxygenation in lipoxygenase and cyclooxygenase catalysis. Chemistry & Biology. 2007;14(5):473-488.

    Not in our library10.1016/j.chembiol.2007.04.007

  176. 176.

    Dubois R. N., Abramson S. B., Crofford L., et al. Cyclooxygenase in biology and disease. The FASEB Journal. 1998;12(12):1063-1073.

    Not in our library10.1096/fasebj.12.12.1063

  177. 177.

    Chandrasekharan N. V., Dai H., Roos K. L. T., et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(21):13926-13931.

    Not in our library10.1073/pnas.162468699

  178. 178.

    Schwab J. M., Schluesener H. J., Meyermann R., Serhan C. N. COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics? Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2003;69(5):339-343.

    Not in our library10.1016/j.plefa.2003.07.003

  179. 179.

    Parfenova H., Levine V., Gunther W. M., Pourcyrous M., Leffler C. W. COX-1 and COX-2 contributions to basal and IL-1β-stimulated prostanoid synthesis in human neonatal cerebral microvascular endothelial cells. Pediatric Research. 2002;52(3):342-348.

    Not in our library10.1203/00006450-200209000-00006

  180. 180.

    Kuwano T., Nakao S., Yamamoto H., et al. Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. The FASEB Journal. 2004;18(2):300-310.

    Not in our library10.1096/fj.03-0473com

  181. 181.

    Fosslien E. Molecular pathology of cyclooxygenase-2 in neoplasia. Annals of Clinical and Laboratory Science. 2000;30(1):3-21.

    Not in our library

  182. 182.

    Bostrom P. J., Aaltonen V., Soderstrom K. O., Uotila P., Laato M. Expression of cyclooxygenase-1 and -2 in urinary bladder carcinomas in vivo and in vitro and prostaglandin E2 synthesis in cultured bladder cancer cells. Pathology. 2001;33(4):469-474.

    Not in our library10.1080/00313020120083188

  183. 183.
    Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer · 2000
    No notice
  184. 184.

    Sackett M. K., Bairati I., Meyer F., et al. Prognostic significance of cyclooxygenase-2 overexpression in glottic cancer. Clinical Cancer Research. 2008;14(1):67-73.

    Not in our library10.1158/1078-0432.ccr-07-2028

  185. 185.

    Hwang D., Scollard D., Byrne J., Levine E. Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. Journal of the National Cancer Institute. 1998;90(6):455-460.

    Not in our library10.1093/jnci/90.6.455

  186. 186.

    Sales K. J., Katz A. A., Howard B., Soeters R. P., Millar R. P., Jabbour H. N. Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. Cancer Research. 2002;62(2):424-432.

    Not in our library

  187. 187.

    Wilson A. J., Fadare O., Beeghly-Fadiel A., et al. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer. Oncotarget. 2015;6(25):21353-21368.

    Not in our library10.18632/oncotarget.3860

  188. 188.

    Sugimoto T., Koizumi T., Sudo T., et al. Correlative expression of cyclooxygenase-1 (Cox-1) and human epidermal growth factor receptor type-2 (Her-2) in endometrial cancer. The Kobe Journal of Medical Sciences. 2007;53(5):177-187.

    Not in our library

  189. 189.

    Sankhasard S., Lertprasertsuk N., Vinitketkumnuen U., Cressey R. Expression of cyclooxygenase-1 and -2 and clinicopathologic features of colorectal cancer in northern Thailand. Asian Pacific Journal of Cancer Prevention. 2004;5(1):44-49.

    Not in our library

  190. 190.

    Chariyalertsak S., Sirikulchayanonta V., Mayer D., et al. Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma. Gut. 2001;48(1):80-86.

    Not in our library10.1136/gut.48.1.80

  191. 191.

    Bach A. W., Lan N. C., Johnson D. L., et al. cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(13):4934-4938.

    Not in our library10.1073/pnas.85.13.4934

  192. 192.

    Edmondson D. E., Binda C., Wang J., Upadhyay A. K., Mattevi A. Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases. Biochemistry. 2009;48(20):4220-4230.

    Not in our library10.1021/bi900413g

  193. 193.

    Ramsay R. R., Albreht A. Kinetics, mechanism, and inhibition of monoamine oxidase. Journal of Neural Transmission. 2018;125(11):1659-1683.

    Not in our library10.1007/s00702-018-1861-9

  194. 194.

    Fitzpatrick P. F. Oxidation of amines by flavoproteins. Archives of Biochemistry and Biophysics. 2010;493(1):13-25.

    Not in our library10.1016/j.abb.2009.07.019

  195. 195.

    Bortolato M., Chen K., Shih J. C. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Advanced Drug Delivery Reviews. 2008;60(13-14):1527-1533.

    Not in our library10.1016/j.addr.2008.06.002

  196. 196.

    Maggiorani D., Manzella N., Edmondson D. E., et al. Monoamine oxidases, oxidative stress, and altered mitochondrial dynamics in cardiac ageing. Oxidative Medicine and Cellular Longevity. 2017;2017:8.

    Not in our library10.1155/2017/3017947

  197. 197.

    Wu J. B., Shao C., Li X., et al. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. The Journal of Clinical Investigation. 2014;124(7):2891-2908.

    Not in our library10.1172/jci70982

  198. 198.

    Liu F., Hu L., Ma Y., et al. Increased expression of monoamine oxidase A is associated with epithelial to mesenchymal transition and clinicopathological features in non-small cell lung cancer. Oncology Letters. 2018;15(3):3245-3251.

    Not in our library10.3892/ol.2017.7683

  199. 199.

    True L., Coleman I., Hawley S., et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(29):10991-10996.

    Not in our library10.1073/pnas.0603678103

  200. 200.

    Sun W. Y., Choi J., Cha Y. J., Koo J. S. Evaluation of the expression of amine oxidase proteins in breast cancer. International Journal of Molecular Sciences. 2017;18(12):p. 2775.

    Not in our library10.3390/ijms18122775

  201. 201.

    Peehl D. M., Coram M., Khine H., Reese S., Nolley R., Zhao H. The significance of monoamine oxidase-A expression in high grade prostate cancer. The Journal of Urology. 2008;180(5):2206-2211.

    Not in our library10.1016/j.juro.2008.07.019

  202. 202.

    Li J., Yang X. M., Wang Y. H., et al. Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling. Journal of Hepatology. 2014;60(6):1225-1234.

    Not in our library10.1016/j.jhep.2014.02.025

  203. 203.

    Huang L., Frampton G., Rao A., et al. Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events. Laboratory Investigation. 2012;92(10):1451-1460.

    Not in our library10.1038/labinvest.2012.110

  204. 204.
    An indicator of cancer: downregulation of Monoamine Oxidase-A in multiple organs and species · 2008
    Not checked
  205. 205.

    Sood A. K., Bhatty R., Kamat A. A., et al. Stress hormone-mediated invasion of ovarian cancer cells. Clinical Cancer Research. 2006;12(2):369-375.

    Not in our library10.1158/1078-0432.ccr-05-1698

  206. 206.

    Sastry K. S. R., Karpova Y., Prokopovich S., et al. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. Journal of Biological Chemistry. 2007;282(19):14094-14100.

    Not in our library10.1074/jbc.m611370200

  207. 207.

    Grau-Bove X., Ruiz-Trillo I., Rodriguez-Pascual F. Origin and evolution of lysyl oxidases. Scientific Reports. 2015;5(1, article 10568).

    Not in our library10.1038/srep10568

  208. 208.

    Xu J., Li D., Li X., et al. 67 laminin receptor promotes the malignant potential of tumour cells up-regulating lysyl oxidase-like 2 expression in cholangiocarcinoma. Digestive and Liver Disease. 2014;46(8):750-757.

    Not in our library10.1016/j.dld.2014.03.017

  209. 209.

    Park J. S., Lee J. H., Lee Y. S., Kim J. K., Dong S. M., Yoon D. S. Emerging role of LOXL2 in the promotion of pancreas cancer metastasis. Oncotarget. 2016;7(27):42539-42552.

    Not in our library10.18632/oncotarget.9918

  210. 210.

    Shih Y. H., Chang K. W., Chen M. Y., et al. Lysyl oxidase and enhancement of cell proliferation and angiogenesis in oral squamous cell carcinoma. Head & Neck. 2013;35(2):250-256.

    Not in our library10.1002/hed.22959

  211. 211.

    Albinger-Hegyi A., Stoeckli S. J., Schmid S., et al. Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC). International Journal of Cancer. 2010;126(11):2653-2662.

    Not in our library10.1002/ijc.24948

  212. 212.

    Peng L., Ran Y. L., Hu H., et al. Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis. 2009;30(10):1660-1669.

    Not in our library10.1093/carcin/bgp178

  213. 213.

    Scola N., Gorogh T. LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma. Anticancer Research. 2010;30(11):4567-4571.

    Not in our library

  214. 214.

    Leo C., Cotic C., Pomp V., Fink D., Varga Z. Overexpression of Lox in triple-negative breast cancer. Annals of Diagnostic Pathology. 2018;34:98-102.

    Not in our library10.1016/j.anndiagpath.2018.03.009

  215. 215.

    Nakanishi A., Wada Y., Kitagishi Y., Matsuda S. Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases. Aging and Disease. 2014;5(3):203-211.

    Not in our library10.14336/ad.2014.0500203

  216. 216.

    Alvarez-Garcia V., Tawil Y., Wise H. M., Leslie N. R. Mechanisms of PTEN loss in cancer: it’s all about diversity. Seminars in Cancer Biology. 2019.

    Not in our library10.1016/j.semcancer.2019.02.001

  217. 217.

    Chalhoub N., Baker S. J. PTEN and the PI3-kinase pathway in cancer. Annual Review of Pathology. 2009;4(1):127-150.

    Not in our library10.1146/annurev.pathol.4.110807.092311

  218. 218.

    El-Benna J., Dang P. M. C., Gougerot-Pocidalo M. A., Marie J. C., Braut-Boucher F. p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Experimental & Molecular Medicine. 2009;41(4):217-225.

    Not in our library10.3858/emm.2009.41.4.058

  219. 219.

    Leslie N. R., Bennett D., Lindsay Y. E., Stewart H., Gray A., Downes C. P. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. The EMBO Journal. 2003;22(20):5501-5510.

    Not in our library10.1093/emboj/cdg513

  220. 220.
    NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease · 2017
    No notice
  221. 221.

    Haagenson K. K., Wu G. S. Mitogen activated protein kinase phosphatases and cancer. Cancer Biology & Therapy. 2010;9(5):337-340.

    Not in our library10.4161/cbt.9.5.11217

  222. 222.

    Caretta A., Mucignat-Caretta C. Protein kinase a in cancer. Cancers. 2011;3(1):913-926.

    Not in our library10.3390/cancers3010913

  223. 223.

    Kumar R., Gururaj A. E., Barnes C. J. p21-activated kinases in cancer. Nature Reviews Cancer. 2006;6(6):459-471.

    Not in our library10.1038/nrc1892

  224. 224.

    Vurusaner B., Poli G., Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radical Biology & Medicine. 2012;52(1):7-18.

    Not in our library10.1016/j.freeradbiomed.2011.09.035

  225. 225.

    Hussain S. P., Amstad P., He P., et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Research. 2004;64(7):2350-2356.

    Not in our library10.1158/0008-5472.can-2287-2

  226. 226.

    Tan M., Li S., Swaroop M., Guan K., Oberley L. W., Sun Y. Transcriptional activation of the human glutathione peroxidase promoter by p53. Journal of Biological Chemistry. 1999;274(17):12061-12066.

    Not in our library10.1074/jbc.274.17.12061

  227. 227.

    Budanov A. V., Sablina A. A., Feinstein E., Koonin E. V., Chumakov P. M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 2004;304(5670):596-600.

    Not in our library10.1126/science.1095569

  228. 228.

    Suzuki S., Tanaka T., Poyurovsky M. V., et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(16):7461-7466.

    Not in our library10.1073/pnas.1002459107

  229. 229.

    Bensaad K., Tsuruta A., Selak M. A., et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126(1):107-120.

    Not in our library10.1016/j.cell.2006.05.036

  230. 230.

    Hu C. A., Lin W. W., Valle D. Cloning, characterization, and expression of cDNAs encoding human Δ1-pyrroline-5-carboxylate dehydrogenase. Journal of Biological Chemistry. 1996;271(16):9795-9800.

    Not in our library10.1074/jbc.271.16.9795

  231. 231.

    Yoon K. A., Nakamura Y., Arakawa H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. Journal of Human Genetics. 2004;49(3):134-140.

    Not in our library10.1007/s10038-003-0122-3

  232. 232.

    Liu Z., Lu H., Shi H., et al. PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. Cancer Research. 2005;65(5):1647-1654.

    Not in our library10.1158/0008-5472.can-04-1754

  233. 233.

    Giorgio M., Migliaccio E., Orsini F., et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122(2):221-233.

    Not in our library10.1016/j.cell.2005.05.011

  234. 234.

    Polyak K., Xia Y., Zweier J. L., Kinzler K. W., Vogelstein B. A model for p53-induced apoptosis. Nature. 1997;389(6648):300-305.

    Not in our library10.1038/38525

  235. 235.

    Sablina A. A., Budanov A. V., Ilyinskaya G. V., Agapova L. S., Kravchenko J. E., Chumakov P. M. The antioxidant function of the p53 tumor suppressor. Nature Medicine. 2005;11(12):1306-1313.

    Not in our library10.1038/nm1320

  236. 236.

    Vander Heiden M. G., Cantley L. C., Thompson C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033.

    Not in our library10.1126/science.1160809

  237. 237.

    Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314.

    Not in our library10.1126/science.123.3191.309

  238. 238.

    Tong X., Zhao F., Thompson C. B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Current Opinion in Genetics & Development. 2009;19(1):32-37.

    Not in our library10.1016/j.gde.2009.01.002

  239. 239.

    Labak C. M., Wang P. Y., Arora R., et al. Glucose transport: meeting the metabolic demands of cancer, and applications in glioblastoma treatment. American Journal of Cancer Research. 2016;6(8):1599-1608.

    Not in our library

  240. 240.
    HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer · 2018
    Not checked
  241. 241.

    Krasnov G. S., Dmitriev A. A., Sadtritdinova A. F., et al. Evaluation of gene expression of hexokinases in colorectal cancer with the use of bioinformatics methods. Biofizika. 2015;60(6):1050-1056.

    Not in our library

  242. 242.

    Oparina N. Y., Snezhkina A. V., Sadritdinova A. F., et al. Differential expression of genes that encode glycolysis enzymes in kidney and lung cancer in humans. Russian Journal of Genetics. 2013;49(7):707-716.

    Not in our library10.1134/s1022795413050104

  243. 243.

    Krasnov G. S., Dmitriev A. A., Snezhkina A. V., Kudryavtseva A. V. Deregulation of glycolysis in cancer: glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. Expert Opinion on Therapeutic Targets. 2013;17(6):681-693.

    Not in our library10.1517/14728222.2013.775253

  244. 244.

    Snezhkina A. V., Krasnov G. S., Zhikrivetskaya S. O., et al. Overexpression of microRNAs miR-9,-98, and-199 correlates with the downregulation of HK2 expression in colorectal cancer. Molecular Biology. 2018;52(2):190-199.

    Not in our library10.1134/s0026893318020140

  245. 245.

    Snezhkina A. V., Krasnov G. S., Zaretsky A. R., et al. Differential expression of alternatively spliced transcripts related to energy metabolism in colorectal cancer. BMC Genomics. 2016;17(Supplement 14):p. 1011.

    Not in our library10.1186/s12864-016-3351-5

  246. 246.

    Fedorova M. S., Kudryavtseva A. V., Lakunina V. A., et al. Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer. Molecular Biology. 2015;49(4):608-617.

    Not in our library10.1134/s0026893315040044

  247. 247.

    Lee M., Yoon J. H. Metabolic interplay between glycolysis and mitochondrial oxidation: the reverse Warburg effect and its therapeutic implication. World Journal of Biological Chemistry. 2015;6(3):148-161.

    Not in our library10.4331/wjbc.v6.i3.148

  248. 248.

    Fernandez-Marcos P. J., Nobrega-Pereira S. NADPH: new oxygen for the ROS theory of aging. Oncotarget. 2016;7(32):50814-50815.

    Not in our library10.18632/oncotarget.10744

  249. 249.

    Stanton R. C. Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life. 2012;64(5):362-369.

    Not in our library10.1002/iub.1017

  250. 250.

    Holten D., Procsal D., Chang H. L. Regulation of pentose phosphate pathway dehydrogenases by NADP+/NADPH ratios. Biochemical and Biophysical Research Communications. 1976;68(2):436-441.

    Not in our library10.1016/0006-291x(76)91164-5

  251. 251.

    Mullarky E., Cantley L. C., Nakao K., Minato N., Uemoto S. Diverting glycolysis to combat oxidative stress. Innovative Medicine: Basic Research and Development. 2015;3-23.

    Not in our library10.1007/978-4-431-55651-0_1

  252. 252.

    Ghanbari Movahed Z., Rastegari-Pouyani M., Mohammadi M. H., Mansouri K. Cancer cells change their glucose metabolism to overcome increased ROS: One step from cancer cell to cancer stem cell? Biomedicine & Pharmacotherapy. 2019;112, article 108690.

    Not in our library10.1016/j.biopha.2019.108690

  253. 253.
    Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment · 2016
    No notice
  254. 254.

    Whiteside T. L. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904-5912.

    Not in our library10.1038/onc.2008.271

  255. 255.

    Carmeliet P., Jain R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298-307.

    Not in our library10.1038/nature10144

  256. 256.

    Frisch J., Angenendt A., Hoth M., Prates Roma L., Lis A. STIM-Orai channels and reactive oxygen species in the tumor microenvironment. Cancers. 2019;11(4):p. 457.

    Not in our library10.3390/cancers11040457

  257. 257.

    Bhome R., Bullock M. D., Al Saihati H. A., et al. A top-down view of the tumor microenvironment: structure, cells and signaling. Frontiers in Cell and Developmental Biology. 2015;3:p. 33.

    Not in our library10.3389/fcell.2015.00033

  258. 258.

    Wang M., Zhao J., Zhang L., et al. Role of tumor microenvironment in tumorigenesis. Journal of Cancer. 2017;8(5):761-773.

    Not in our library10.7150/jca.17648

  259. 259.

    Sun Y. Tumor microenvironment and cancer therapy resistance. Cancer Letters. 2016;380(1):205-215.

    Not in our library10.1016/j.canlet.2015.07.044

  260. 260.

    Yu Y., Cui J. Present and future of cancer immunotherapy: a tumor microenvironmental perspective. Oncology Letters. 2018;16(4):4105-4113.

    Not in our library10.3892/ol.2018.9219

  261. 261.

    Bienert G. P., Schjoerring J. K., Jahn T. P. Membrane transport of hydrogen peroxide. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2006;1758(8):994-1003.

    Not in our library10.1016/j.bbamem.2006.02.015

  262. 262.

    Henzler T., Steudle E. Transport and metabolic degradation of hydrogen peroxide in Chara corallina: model calculations and measurements with the pressure probe suggest transport of H2O2 across water channels. Journal of Experimental Botany. 2000;51(353):2053-2066.

    Not in our library10.1093/jexbot/51.353.2053

  263. 263.

    Hara-Chikuma M., Satooka H., Watanabe S., et al. Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis. Nature Communications. 2015;6(1, article 7454).

    Not in our library10.1038/ncomms8454

  264. 264.

    Laukkanen M. O. Extracellular superoxide dismutase: growth promoter or tumor suppressor? Oxidative Medicine and Cellular Longevity. 2016;2016:9.

    Not in our library10.1155/2016/3612589

  265. 265.

    Nauseef W. M. Detection of superoxide anion and hydrogen peroxide production by cellular NADPH oxidases. Biochimica et Biophysica Acta (BBA) - General Subjects. 2014;1840(2):757-767.

    Not in our library10.1016/j.bbagen.2013.04.040

  266. 266.

    Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer Research. 2014;34(4):1467-1482.

    Not in our library

  267. 267.

    Chan J. S. K., Tan M. J., Sng M. K., et al. Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress. Cell Death & Disease. 2018;8(1, article e2562).

    Not in our library10.1038/cddis.2016.492

  268. 268.

    Paardekooper L. M., Vos W., Bogaart G. Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget. 2019;10(8):883-896.

    Not in our library10.18632/oncotarget.26608

  269. 269.

    Birben E., Sahiner U. M., Sackesen C., Erzurum S., Kalayci O. Oxidative stress and antioxidant defense. The World Allergy Organization Journal. 2012;5(1):9-19.

    Not in our library10.1097/wox.0b013e3182439613

  270. 270.

    Onyango A. N. Endogenous generation of singlet oxygen and ozone in human and animal tissues: mechanisms, biological significance, and influence of dietary components. Oxidative Medicine and Cellular Longevity. 2016;2016:22.

    Not in our library10.1155/2016/2398573

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