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The Role of Nitric Oxide in Cancer: Master Regulator or NOt?

Faizan H. Khan, Eoin Dervan, Dibyangana D. Bhattacharyya and 3 more

International Journal of Molecular Sciences · 2020 · Review · CC BY

doi:10.3390/ijms21249393

Abstract

Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Nitric oxide (NO) is a biologically unstable, lipophilic, extremely diffusible, free radical that regulates numerous biological functions. Since discovery of NO in the cardiovascular system as the endothelium-derived relaxing factor (EDRF), researchers have identified roles for NO in a wide range of pathophysiological processes. Although dietary nitrate and nitrite (NO2−/NO3−) are precursors for a certain amount of NO biosynthesis, NO is generated primarily by three different NO synthase (NOS) enzymes: the neuronal (nNOS/NOS1), inducible (iNOS/NOS2), and endothelial (eNOS/NOS3) isoforms. In the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen (O2), NOS oxidises L-arginine to form L-citrulline and NO (Figure 1a). Constitutively expressed eNOS and nNOS facilitate low levels of NO production in a calcium-dependent manner, while iNOS produces high levels of NO in a calcium-independent manner.

NO typically reacts facilely with other molecules that contain unpaired electrons such as free radicals and transition metals. In addition, the oxidation products of NO are also capable of interacting with other biological molecules and can result in toxicity. NO takes part in biological reactions by three main processes:Diffusion

Diffusion

As a small, neutral molecule, NO rapidly enters cells by simple diffusion. The main intracellular targets are heme proteins, but NO can also react with non-heme iron or protein-based free radicals such as the tyrosyl radical of ribonucleotide reductase, a rate limiting enzyme in DNA synthesis. Autoxidation

Autoxidation

The reaction of NO with nitrogen dioxide (NO2) produce nitrous anhydride (N2O3), which is converted to nitrite in aqueous systems (Equation (1)). Reaction with superoxide to form peroxynitrite

Reaction with superoxide to form peroxynitrite

NO reacts with superoxide (O2−) to yield peroxynitrite (ONOO−) (Equation (2)). This species has varied reactivity, but a major biological pathway involves rapid interaction with carbon dioxide to form nitrosoperoxycarbonate (ONOOCO2-). While this reactive species leads mostly to nitrate (Equation (3)), it can also generate the carbonate and NO2 radicals (Equation (4)), which can react with a wide range of biomolecules including nucleic acids, amino acids, lipids, metal containing proteins. Protonation of peroxynitrite can also lead to radical formation through homolytic cleavage (Equation (5)), although, again, isomerisation to nitrate is the major pathway.

The concentration and time-dependent effects of NO and NO-derived cellular adducts determine its biochemical and phenotypic consequences in cancer pathogenesis (Figure 1c). Low levels of NO (picomolar to nanomolar) have direct effects on cellular function by promoting cell proliferation and anti-apoptotic responses. The reaction between NO and organic free radicals or with metal complexes represents its direct effect. High levels of NO (micromolar) have been shown to exert indirect effects and induce cell cycle arrest, apoptosis and senescence through both oxidative and nitrosative stresses. The presence of other free radicals also influences NO signalling through reduction of the cellular NO level. Thus, the imbalance between the production and consumption rates of free radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS) can cause oxidative and nitrosative stress. Cellular accumulation of ROS and RNS is involved in carcinogenesis. However, increased chemical stress may cause more deleterious effects in cancer cells such as protein modification, lipid peroxidation and DNA damage.

Although NO is a well-known signalling molecule, understanding the precise molecular effects it exerts will help elucidate its tremendous clinical potential in the diagnosis and treatment of cancer. Thus, here, we review the various actions of NO and its by-products in cancer and discuss how they may be leveraged as a novel therapeutic strategy in personalised cancer treatment.

2. NO Cell Signalling

NO-mediated pathways are regulated in either a cyclic guanosine monophosphate (cGMP)-dependent or cGMP-independent manner (Figure 1b). Although cGMP-dependent pathways have long been found to mediate several cellular processes, cGMP-independent reactions have also gained significant attention. These pathways involve different targets and varied modification processes.

NO produced by nNOS and eNOS typically exerts its effects via cGMP-dependent pathways, while the higher levels of NO produced by iNOS lead to protein modifications by RNS.

2.1. cGMP-Dependent Pathway

In the NO-mediated cGMP-dependent pathway, guanylate cyclase (GC) converts guanosine triphosphate (GTP) into the secondary messenger cGMP, which triggers the activation of cGMP-dependent protein kinases (PKG/PKA), cGMP regulated phosphodiesterases (PDE), and cyclic-nucleotide gated (CNG) ion channels. These, in turn, impact vital biological processes, such as smooth muscle relaxation and regulation of blood pressure, platelet aggregation and disaggregation, and neurotransmission both peripherally and centrally, in the processes of long-term potentiation and depression. The involvement of cGMP in growth inhibition has been identified in vascular smooth muscle cells (VSMCs), in which GC interacts with NO produced by eNOS with a subsequent increase in cGMP and repression of the epidermal growth factor signalling pathway. The increased cGMP phosphorylates target proteins such as the inositol 1,4,5-triphosphate receptor, resulting in a decrease in Ca2+ concentration and, in due course, smooth muscle relaxation. The phosphorylation and subsequent degradation of β-catenin by protein kinase G (PKG) is also mediated by cGMP leading to the downregulation of growth-promoting and apoptosis-inhibiting proteins, including cyclin D1, c-myc, and survivin. Similarly, NO produced by nNOS in neuronal cells of the retina and in the olfactory region attenuates the synaptic behaviour of NO-sensitive neurons where they are engaged in visual phototransduction and olfaction.

2.2. cGMP-Independent Pathway

The cGMP-independent pathway wields it effects through post-translational modifications of proteins, particularly at reactive thiol (RSH) and amine (RR’NH) sites, producing S-nitrosothiols (RSNO), and N-nitrosoamines (RR’NNO), respectively. The S-nitrosation of cysteine residues has been found to regulate proteins and enzymes including NF-κB, AP-1 and CREB. Various signalling cascades including G-proteins, the Ras pathway, mitogen-activated protein kinases (MAPK) signalling, and the phosphatidylinositol-3 kinase (PI3K) pathway are also regulated by S-nitrosation of their components. S-nitrosation also regulates many NO-dependent signalling pathways, including Ca2+-dependent potassium channel induction in vascular smooth muscle, repression of mitochondrial cytochrome oxidase, bile acid secretion by Na+-taurocholate co-transporting polypeptide (NTCP) in hepatocytes, and calcium-release channels such as the ryanodine receptor. RR’NNO can act as carcinogens. In particular, tobacco associated RR’NNO such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are key players in the development of lung cancer and also promote the development of metastasis.

3. Role of NO in Cancer Biology

The role of NO in biological process depends on its source of generation, duration, and spatial concentration. At lower concentration, NO exerts cytoprotective effects and triggers carcinogenesis through activation of oncogenic pathways. However, at higher concentration, NO has been shown to produce cytotoxic effects in cancer cells and induce apoptosis. The pro- and anti-tumour effects of NO in cancer biology play important roles by shifting the cellular response to stressors such as DNA damage, oncogene activation, altered cell metabolism and deregulating DNA repair enzymes and tumour suppressor genes, in addition to modulation of apoptotic and metastatic processes.

3.1. Genotoxicity and Mutagenesis

NO-mediated genotoxicity occurs due to the deamination of DNA bases, oxidation of bases and deoxyribose, strand breaks, and multiple types cross-linking events. These reactions can result in direct genotoxicity induced by the deamination of amines with N2O3 and formation of peroxynitrite, or by indirect genotoxicity due to nitrosamine activation, apoptosis, DNA repair enzyme inhibition, or lipid peroxidation-induced DNA damage.

NO oxidises to form RNS that nitrosate primary heterocyclic amines of DNA bases (Equation (6)). Such nitrosated amines are susceptible to rapid deamination through isomerisation to a diazohydroxide followed by dehydration to a highly reactive diazonium ion (Equation (7)). Deamination plays a key function in the deleterious consequences of NO that could be important to the mutational landscape and heterogeneity observed within tumours. Deamination of guanine to xanthine causes depurination to create abasic sites in DNA, resulting in single strand breaks or misrepair. NO-induced mutations were shown to be induced in TK6 cells, calf thymus DNA, yeast RNA, and bovine liver transfer RNA following NO treatment in vitro, resulting in the formation of a significant amount of xanthine and hypoxanthine. Furthermore, macrophages stimulated with LPS and IFN-γ significantly induced the production of xanthine that could be repressed by the NOS inhibitor N-methyl-l-arginine monoacetate (NMA).

One mutagenic example of NO in mammalian cells its targeting codon 248 (CGG) in the p53 gene, which is one of the most commonly mutated genes in cancer. Methylation of cytosine followed by its deamination results the formation of thymine. The mutagenicity of NO has been demonstrated to cause deamination in CpG sites of the p53 gene, resulting in a G-C → A-T transition, which plays a crucial role in different human cancers including colon, liver, breast, and lung. The pattern of NO-induced point mutations was measured in the supF gene via deamination of either A or G that induce A:T → G:C transitions followed by G:C → A:T transitions.

The reaction of N2O3 with secondary amines can form carcinogenic N-nitrosamines that metabolise to strong alkylating electrophiles that can alter the N-7 and O-6 positions of guanine and the N-3 position of adenine in DNA. Alteration at the O6 position in guanine is prone to mutation and causes G→A transitions during DNA replication.

NO2 is also an NO-derived strong oxidant, which oxidises protein and non-protein thiols, protein sulphides, lipids, and low density lipoproteins. Exposure of DNA to NO2 leads to the formation of 8-hydroxydeoxyguanosine and 8-nitroguanine from guanosine. Reaction of NO with O2- can lead to medication of phenolic compounds to form highly mutagenic nitrated and hydroxylated product such as 8-nitroguanine and 4,5-dihydro-5-hydroxy-4-(nitrosooxy) guanine, which depurinate rapidly and cause transversion mutations (mainly G→T) at G-C pairs. However, trace metals can change the chemistry to produce nitration and/or hydroxylation of DNA bases. NO-induced oxidative deamination in the DNA of activated macrophages has been quantified by measuring 8-oxoguanine and 5-(hydroxymethyl) uracil formation. The role of NO in both deamination and oxidation reactions was confirmed by NOS-inhibition, which suppressed both xanthine and 8-oxoguanine formation. Intracellular NO2 formation can also induce DNA single-strand breaks either by direct DNA nicking or involve other cellular factors such as abasic repair enzymes (i.e., activation of exonucleases and/or suppression of ligase and/or polymerases).

The genotoxic effects of NO were suspected due to the fact that fluxes of O2- form much more quickly than NO fluxes in activated macrophages and neutrophils. The genotoxic potential of NO metabolites has been confirmed by NOS inhibitors that prevented DNA damage in activated macrophages. The reaction of RNS with sulphhyldryl-containing peptides forms nitrosothiols, altering the function of ion channels, p21ras, protein tyrosine phosphatates, and cyclooxygenases. S-Nitrosation of glutathione (GSH) induces apoptosis in epithelial cells, macrophage-like cells such as RAW 264.7 and renal mesangial cells by induction of nuclear chromatin condensation, DNA fragmentation and p53 accumulation. The formation of the malondialdehyde (MDA), a lipid peroxidation product induced by peroxynitrite is mutagenic in bacterial and mammalian systems and causes frameshifts and base-pair substitutions. DNA damaging activity of NO and its metabolites was also increased due to inhibition of DNA repair proteins such as zinc finger-containing formamidopyrimidine DNA glycosylase (Fpg protein) and O6-methylguanine -DNA-methyltransferase by S-nitrosation of proteins.

3.2. DNA Damage Repair (DDR)

As described above, NO and its derivatives induce DNA damage leading to activation of DDR signalling networks. The DDR response is regulated by five main DNA repair mechanisms that include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and the two double strand break repair pathways: non-homologous end-joining (NHEJ) and homology directed repair (HDR) (Figure 2). The NHEJ and HDR are also involved in the Fanconi Anaemia (FA) pathway to achieve interstrand DNA crosslink repair. More than 150 proteins have been identified in DDR mechanisms, which control the progression of neurological diseases, aging, cancer risk, cancer therapy outcomes, inflammation, and other genetic syndromes with a variety of distinct phenotypes.

The NER pathway is a complex process involving more than 30 proteins that work to eliminate bulky DNA lesions by special endonucleases (Figure 2b). NER includes two distinct pathways, i.e., global genome-NER (GG-NER) and transcription coupled-NER (TC-NER). GG-NER is regulated by the xeroderma pigmentosum group c protein, which recognises DNA damage and recruits other repair machinery, while TC-NER is initiated by blocking RNA polymerase II activity at altered areas undergoing transcription. Both GG-NER and TC-NER involve the basic mechanism: (1) recognition of the damaged sites (in transcribed and non-transcribed regions of the genome, respectively); (2) verification of DNA damage; (3) excision of damaged oligomers; and (4) gap filling by ligating intact molecules. Defects in the NER pathway causes rare autosomal recessive diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). NO was shown to inhibit DNA-adduct NER in human fibroblasts, including UVC and cisplatin derived DNA adducts. Treatment with iNOS inhibitors increased NER activity. In contrast, NO did not impact BER in the same system.

The BER pathway specifically repairs N-alkylation DNA damage such as N7MeG, N3MeA, and N3MeG, in which DNA glycosylases search the damage sites in the genome, creating an apurinic/apyrimidinic (AP) site. Further, AP-endonuclease (APE) cleave the DNA at AP sites to form one nucleotide gap which is filled with the correct nucleotide by polymerase-β. NO has previously been reported to induce nuclear export of APE to the cytoplasm, via S-nitrosation of APE1 at cysteine 93 and 310, which may disrupts its DNA repair function. Finally, DNA ligase IIIα complex containing XRCC1 protein seals the left-over nick in the DNA backbone (Figure 2a). Defects in this BER enzyme are associated with premature aging, cancer, and neurodegenerative diseases. However, the exact mechanisms of BER dysregulation are not well known. Thus, downregulation of BER components has gained significant clinical interest in cancer therapy, using small molecular inhibitors in combination with radio- and/or chemotherapeutic agents. iNOS overexpression in cholangiocarcinoma cells was found to inhibit 8-oxodeoxyguanine base excision DNA repair. The inhibitory effect of iNOS could be reversed with NO scavengers but not sGC inhibitors indicating that this was not mediated by cGMP-dependent NO signalling.

Nitrosative deamination of guanine gives rise to two products, xanthine (Xan) and Oxa. Oxa can further react with spermine to form Oxa-spermine cross-link adducts (Oxa-Sp). Nakano et al. examined the ability of NER and BER enzymes to repair Oxa and Oxa-Sp in E. coli and human systems and found that Oxa and OXA-Sp DNA were preferentially repaired by NER, with BER enzymes only having weak reparatory activity. This suggests that the nature of NO DNA adducts may influence which excision repair pathway works optimally. Mutumba et al. (2011) found that XRCC1 facilitates alkyl adenine DNA glycosylase (AAG) initiated excision of two key NO-induced DNA lesions: 1,N(6)-ethenoadenine and hypoxanthine, indicating that depending on the type of DNA damage that occurs BER can be activated in response to NO related DNA damage, while its effectiveness also depends on the type of damage involved (guanine versus adenine). S-nitrosation of AAG has also been found to increase the activity of AAG. This coupled with the impact of NO on APE export to the cytoplasm may lead to BER enzymatic machinery imbalance, disrupting the effectiveness of BER in NO related DDR.MMR fixes replication associated errors that can arise due to insertion, deletion, and mis-incorporation of bases in the newly synthesised strand during DNA replication (Figure 2c). The MutSα complex (MSH2 and MSH6) or MutSβ complex (MSH2 and MSH3) detect and bind with base-base mismatches and insertion, deletion loops (IDLs), and interact with the N-terminal domain of any MutL homologues such as MutLα (MLH1-PMS2), MutLβ (MLH1-MLH3), and MutLγ (MLH1-PMS1). The C-terminal of MutL homologues has latent endonuclease activity that recruits proliferating cell nuclear antigen (PCNA), replication factor C subunit 1 (RFC), and exonuclease (EXO1) to perform the excision step. DNA polymerase-δ facilitates high-fidelity DNA synthesis, while DNA ligase I/IV seals the nick. MMR dysfunction results an autosomal-dominant inherited cancer predisposition syndrome (also called Lynch syndrome) that increases the prevalence of sporadic cancers. MSH2 and MSH6 deficient colon cancer cells exhibit increased rates of NO induced mutations compared to MSH2 and MSH6 proficient cell lines, indicating that MMR can play a role in repairing NO related DNA damage.

Double stranded breaks (DSBs) are highly deleterious and the most lethal of all DNA lesions. Thus, it is important to understand both HDR- and NHEJ-mediated DSB repairs (Figure 2d). HDR is believed to result in error free DSB repair and healthy cell growth, while NHEJ is error prone and has higher potential for the introduction of malignancy-related mutations. These two pathways are influenced by many regulatory mechanisms.

NHEJ is responsible for fixing many two-ended DSBs in eukaryotic cells. NHEJ is initiated with the fast and strong-affinity binding of the Ku70-Ku80 heterodimer (Ku) to DNA ends which prevents DNA end resection and recruits the DNA-dependent protein kinase (DNA-PK) holoenzyme. Subsequently, DNA-PK facilitates the following key functions in NHEJ: (i) activating the DNA nucleases (e.g., ARTEMIS) to process the broken ends and find cohesive nucleotides; (ii) filling the small single-strand gaps in DSB ends by polymerases (e.g., Polμ and Polλ); and (iii) catalysing the DSB ligation by DNA ligase complex consisting of DNA ligase IV, XRCC4, XLF, and PAXX. Mutations in NHEJ components cause several abnormal conditions such as severe combined immunodeficiency (SCID), microcephalic primordial dwarfism, and isolated radiation hypersensitivity/malignancy predisposition. Xu et al. reported that NO increases the expression of DNA-PK catalytic subunit thus contributing to DNA-PK activity and NHEJ repair.

HDR involves a high-fidelity DSB repair type that plays a major role in DNA repair, DNA replication, meiotic chromosome separation, and telomere conservation. HDR is facilitated by the MRE11-RAD50-NBS1 (MRN) complex, CtIP, and BRCA1. The Mre11-Rad50 (MR) subcomplex shows a dual endonuclease (DNA2) and EXO1 activity to form a short 3′ ssDNA overhang. ssDNA tail degradation by the MRN complex is stopped by binding of replication protein A (RPA) at the 3′ ssDNA tails that create hairpin-capped ends to hinder HR repair. Furthermore, BRCA2 in association with BRCA1 and PALB2 brings RAD51 monomers to ssDNA to remove RPA, resulting in the formation of RAD51 presynaptic filaments to seek out homologous sequences and strand invasion. The invading strand is extended at 3′ end, either by replicative DNA polymerases (POL δ and ε) or translesion DNA polymerases (POL η and κ), resulting in displacement loop (D-loop) formation. D-loop structures can be unravelled by the following homologous repair (HR) pathways: double-strand break repair (DSBR), synthesis-dependent strand annealing (SDSA) or break induced replication (BIR). NO can impact the activation of the HDR by inhibiting BRCA1 expression via NO activation of PP2A. This leads to RBL2 dephosphorylation, altering RBL2/E2F complexes to favour RBL2/E2F4 complexes which repress the BRCA1 promoter. Intriguingly, Mujoo et al. reported that pluripotent stem cell differentiation is mediated in part by the NO-cGMP pathway. This increases DNA damage, but also represses RAD51 and BRCA1, instead favouring NHEJ with 53BP1 activation. Similar effects of NO have been seen in A549 lung carcinoma cells adapted to chronic NO exposure.

3.3. Cell Cycle Arrest

NO induced genotoxicity triggers signal transduction cascades that regulate cell cycle checkpoints that allow for activation of restorative DDR machinery. The term checkpoint is defined by the switch between the G1/S, intra-S, and G2/M cell cycle phases. The DNA damage checkpoint is controlled by complex signalling pathways, consisting of three main components: sensors of damage, signal transducers, and effectors that triggers cell cycle arrest, apoptosis, DNA repair, and/or activation of damage induced transcription machinery.

The DNA damage checkpoints are initiated and sensed by essential factors such as Rad9, Rad1, Hus1, and Rad17. The Rad9, Hus1, and Rad1 orthologues structurally resemble proliferating nuclear antigen (PCNA) and create a homotrimeric Rad9–Hus1–Rad1 sliding clamp (9-1-1 complex) that is loaded around the DNA at ongoing DNA replication sites. The RFC complex works as a clamp loader for PCNA, which comprises four small subunits (p36, p37, p38, and p40) and one large subunit (pl40). However, for the 9-1-1 complex, Rad17 interacts with the four small subunits of RFC to make an alternative clamp loader complex (Rad17–RFC). The chromatin-bound 9-1-1 complex phosphorylates and activates the checkpoint-signalling cascade mediated by ataxia telangiectasia mutated (ATM) and ATM and Rad3 related (ATR) proteins. ATM and ATR are members of the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family which belong to the serine/threonine protein kinase (270–450 kDa) superfamily that transmit the damage signal to the effector checkpoint kinases 1 and/or 2 (Chk1/Chk2). In addition, mediator proteins including BRCA1, Claspin, p53 binding protein1 (53BP1), topoisomerase binding protein1 (TopBP1), and mediator of DNA damage checkpoint1 (MDC1) have also been implicated in the DNA damage response. Finally, the phosphorylation of the cell division cycle proteins (Cdc25A, Cdc25B, and Cdc25C) by Chk1/Chk2 or dephosphorylation of Cdc25A–C regulates cyclin/CDK complexes that co-ordinate G1/S, intra-S, and G2/M transitions (Figure 3).

Cells exposed to genotoxic agents in early to mid G1 phase may trigger ATM to phosphorylate and activate Chk2. Activated Chk2 facilitates the phosphorylation of Cdc25A, which causes its ubiquitination and proteasomal degradation. Cdc25A degradation blocks Cdk2 activation preventing Cdc45 loading onto chromatin. The failure of Cdc45 loading onto chromatin stops the recruitment of DNA polymerase α, resulting in cell cycle arrest at the G1/S boundary. Further post-transcriptional modification of p53 is required to maintain this arrest. The nuclear export of p53 and its degradation is inhibited by its phosphorylation on Ser15 by ATM or ATR and on Ser20 by Chk1. Phosphorylation and ubiquitination of ubiquitin ligase Mdm2 also leads to the stabilisation and accumulation of p53 protein in the nucleus. Nuclear accumulation of p53 triggers p21 to bind and suppress the activity of Cdk2/cyclin A/E complexes, thereby inhibiting G1/S transition. In addition, the binding of p21 to the cyclin D–Cdk4 complex suppress the Rb/E2F pathway by phosphorylating Rb protein. When cells experience genotoxicity in S phase, the intra S phase checkpoint interrupts the cell cycle through two different pathways: ATM/ATR–Chk1–Cdc25A and ATM–NBS1–SMC1. In the first pathway, ATR phosphorylates Chk1 which in turn phosphorylates Cdc25A, resulting its proteasomal degradation. Loss of Cdc25A inactivates cyclin E–Cdk2 and prevents the loading of Cdc45 onto chromatin, thus delaying DNA replication to allow repair. In the second pathway, ATM together with Chk2 activate the Nbs1–Mre11–Rad50 complex and intra-S checkpoint. Other proteins such as 53BP1, BRCA1, and MDC1 also mediate in the intra-S checkpoint activation. NO has context dependent effects on cell cycle control. Under chronic inflammation conditions such as ulcerative colitis (a risk factor for colorectal cancer), NO activation of p53 has been shown to be dependent on ATM and ATR and engages a p53/p21 dependent G2/M checkpoint, which would allow DNA repair of free radical-induced DNA damage. A similar mechanism is seen in neuroblastoma where NO induced an ATR-dependent activation of p53 on Ser15. Of therapeutic relevance was that in this model, neuroblastoma cells were sensitised to irradiation.

When DNA damage occurs in G2 phase, the G2/M checkpoint interrupts the cell cycle to stop the cell from entering mitosis (M-Phase). In response to DNA damage, activated ATM transmits two simultaneous cascades that ultimately facilitates the inactivation of the cdc2/Cyclin B complex. In the first cascade, activated Chk1 phosphorylates Cdc25A, which leads to its proteasomal degradation, resulting in the inhibition of Cdc2/cyclin B. In the second cascade, phosphorylation of p53 by activated Chk1 and its dissociation from MDM2 induces its nuclear accumulation and stabilisation, leading to the stimulation of many downstream target genes to block the entry into mitosis including. p53 target genes facilitating this block include 14-3-3 sigma which ties with phosphorylated Cdc2/cyclin B complex to facilitate its nuclear export, GADD45 which induces the dissociation of the Cyclin B-cdc2 complex, and p21 which inhibits a subset of cyclin-dependent kinases such as cdc2. In addition, different isoforms of p38-MAPK (mainly α and γ) induce the G2/M checkpoint by inhibiting Cdc25B. NO-donors given at therapeutic levels induce cell cycle arrest and apoptosis. The NO-donor JS-K induced G2 cell cycle arrest in HBV-positive hepatocellular carcinoma cells via activation/phosphorylation of ATM/ATR/Chk1/Chk2 and led to caspase activation and apoptosis. Similar effects of JS-K were observed in multiple myeloma. NO-donating aspirin also induces G2/M phase arrest resulting in increased cyclin B1 expression and CDK1 phosphorylation concomitant with decreased cyclin D1 and cdc25.

3.4. Apoptotic Effects

Nitrosative DNA damage activates complex signalling networks that induce cells to undergo DNA repair, enter terminal differentiation via senescence, or, if the damage is too severe, undergo apoptosis (Figure 4). NO can also activate telomerase and delay endothelial cell senescence. Oestradiol and eNOS together regulate telomerase catalytic subunit (hTERT) promoter activity. Cellular apoptosis is regulated by crosstalk between death receptor and mitochondrial signalling pathway. The death receptor or extrinsic pathway regulates cell death facilitated by the binding of specific death ligands to their corresponding cell surface receptors such as Fas, TNFR, CD95, Apo1, and the DR3/4/5, and the receptor for TRAIL. Ligand binding to the trimerised receptor at the cell surface triggers downstream pathways via the recruitment of intracellular adapter molecules like FADD (fas-associated death domain protein) and TRADD (TNF-related death domain protein). These adapter molecules transmit death signals by stimulating proteolytic enzymes such as cysteine proteases (e.g., caspases), which are essential for the cleavage of different intracellular substrates and DNA degradation. In the mitochondrial/intrinsic pathway, secondary messengers such as NO and pro-apoptotic proteins (Bax, Bak, Bid, and caspases) lead to mitochondrial membrane permeabilisation through the permeability transition pore (PTP) complex that allows the subsequent release of mitochondrial cytochrome c and other pro-apoptotic molecules such as SMAC/DIABLO, AIF (apoptosis inducing factor), and intra-mitochondrial caspases into the cytoplasm. Cytochrome c then associates with the adapter protein apoptotic protease activating factor (Apaf1) and induces formation of the Apoptosome complex in the cytoplasm which cleaves procaspase-9 to active caspase-9. Caspase-9 in turn triggers procaspase-3 and other executioner caspases that induce apoptotic death by cleavage of other death substrates.

Whether NO induces pro- or anti-apoptotic responses depends on the source of NO, its concentration, and the duration of NO flux. Low levels of NO inhibit apoptosis by activating guanylyl cyclase (GC), inducing the heat shock protein 70 (Hsp 70) response and inhibiting pro-apoptotic proteins such as Bax, in several mammalian cells, including endothelial cells, neural cells, pancreatic islets and many tumour cells (e.g., human ovarian cancer cells). NO exerts most of its anti-apoptotic physiological responses by cGMP-dependent mechanisms or post-translational modifications that upregulate the intracellular antioxidant system (such as glutathione), inactivating caspases, and other apoptotic proteins. cGMP can directly regulate cAMP response element (CRE)-binding protein (CREB) through phosphorylation by cGMP-dependent protein kinase G (PKG) or crosstalk with other signalling pathways such as MAPK, calcineurin, and RhoA pathways.

In contrast, high levels of NO induce apoptosis by activating apoptosis-related receptors such as Fas (also known CD95 or APO-1), death receptor 5, and TNFR1 (also known as p55 or CD120a). Fas activation leads to cellular apoptosis. TNFR1 activation is more complex. In response to NO-mediated DNA damage, SUMOylation and ATM-dependent NEMO phosphorylation (NFκB essential modulator) activates the expression of NFκB-mediated FAS ligand and receptor-interacting protein 1 (RIP1). This leads to NK3-mediated IL8 secretion and recruitment of FADD to trigger caspase 8 activity, resulting in apoptosis. In addition, NO-mediated activation of MAPK pathways including p38-kinase, JNK (c-Jun N-terminal kinase), and ERK1/2 (extracellular regulated kinases) can result in p53 accumulation, caspase activation and cell death. Alternatively, activation of the TNFR can lead to NFκB activation resulting in pro-survival signalling and activation of pro-inflammatory cytokines.

3.5. Angiogenic Effect

Angiogenesis is tightly controlled by the balance between pro-angiogenic and anti-angiogenic factors. In normal circumstances, the balance favours the anti-angiogenic factors, inhibiting angiogenesis. In contrast, during tumour progression, pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and prostaglandins are highly expressed and anti-angiogenic factors such as thrombospondin-1 (TSP1) or endostatin are inhibited (Figure 5).

Most NO-driven angiogenic signals are facilitated at low NO fluxes derived from eNOS that play a vital role in cardiovascular function and blood pressure regulation in the body and regulate blood vessel formation and remodelling in pregnancy. NO/eNOS also regulates tumour angiogenesis and wound healing by inducing several angiogenic factors. The reduced supply of oxygen (hypoxia) and nutrients in rapidly proliferating cells of solid tumours stimulates neovascularisation by promoting the expression of hypoxia-inducible factor-1α (HIF-1α). HIF-1α is stabilised by posttranslational modification of the protein in hypoxic conditions and which allows it to complex with its constitutively expressed β subunit. This heterodimer then translocates to the nucleus where it recruits coactivators CBP/p300 to various promoters containing hypoxia response elements (HREs), leading to the activation of many target genes including VEGF. VEGF is one of the most potent pro-angiogenic factors which mediates the phosphorylation of eNOS at the serine 1177 residue by AKT and a consequent increase in NO production.

NO further promotes HIF-1α stabilisation enhancing the effects of hypoxia in promoting tumour neoangiogenesis. Hypoxia can also facilitate the recruitment of Akt to Ca2+/CaM-activated eNOS by the binding of hsp90, thereby leading to its enzymatic phosphorylation and a long-lasting NO release, even in conditions of low Ca2+. This sustained NO-flux can also inhibit anti-angiogenic thrombospondin-1 (TSP1) and activate the NO/cyclic guanosine monophosphate (cGMP) pathway via ERK phosphorylation within the endothelial compartment to stimulate neovascular growth. Prostaglandin E2 (PGE2) stimulates angiogenesis by enhancing eNOS phosphorylation and triggering the NO/cGMP pathway in endothelial cells of the human umbilical vein. The endothelium-mediated relaxation and the smooth muscle contraction of the rabbit pulmonary artery in response to [Sar9]-SP-sulphone (a stable and selective agonist for the tachykinin NK1 receptor) and prostaglandin E1 (PGE1) was enhanced by sodium nitroprusside (SNP) and abrogated by the eNOS inhibitor, L-NAME.

3.6. Epithelial-to-Mesenchymal Transition (EMT) and Metastatic Effects

Epithelial-to-mesenchymal transition (EMT) is essential to transform benign tumours into aggressive and highly invasive cancers in which the stationary epithelial cells develop the ability to migrate and invade through the surrounding tissue into blood or lymphatic vessels (intravasation), exit the vessel and relocate at distant sites (extravasation), and generate secondary tumour masses at new sites (Figure 5). The EMT process is governed by the downregulation of epithelial markers, e.g. E-cadherin, and upregulation of mesenchymal markers, e.g., vimentin.

A high flux of NO prevents NF-κB activity either by inhibiting the phosphorylation and subsequent loss of IκBα (which prevents the nuclear localisation of NF-κβ), or S-nitrosation of the p50 subunit of NF-κB to reduce its DNA binding activity. Reduced activity of NF-κB also modulates EMT outputs, by controlling downstream EMT-related markers such as Snail, Yin Yang (YY) 1, Raf kinase inhibitor protein (RKIP), phosphatase and tensin homologue (PTEN). High levels of NO can directly inhibit Snail, a master regulator of the EMT transcriptional programme). This leads to the derepression of its targets, e.g., RKIP and E-cadherin, resulting in the suppression of EMT and metastasis. NO-mediated metastasis suppression was demonstrated in vitro by its observed enhancement of the expression of N-myc downstream-regulated gene 1 (NDRG1) in HCC1806 breast cancer cells. This anti-metastatic effect was regulated by incorporation of chelatable iron into a dinitrosyliron complex. Resistant tumour cells are also sensitised by NO to modulate the apoptotic stimuli from chemotherapeutic agents.

NO has been shown to attenuate several transcription factors (SNAI1, SNAI2, ZEB1, and ZEB2), growth factors (EGF, PDGF, HGF) and other signalling molecules like TGF-β, sonic hedgehog (Shh), Wnt/beta-catenin and extracellular matrix (ECM) components which maintain the epithelial morphology and suppress cell migration and invasion. NO has also been reported to suppress tumour growth and metastases in different in vivo and in vitro cancer models. Topical application of NO-exisulind in ultraviolet B-induced skin cancer murine model suppressed EMT by inducing E-Cadherin and inhibiting N-cadherin, fibronectin, SNAIL, Slug and Twist. NO can also attenuate matrix metalloproteinase (MMP, a family of “pro-metastatic” enzymes) activity that is responsible for the degradation of the basement membrane necessary for tissue invasion and tumour cell dissemination. NO can suppress the mRNA-stabilising factor HuR, resulting in the destabilisation of MMP-9 mRNA. IL-2/α-CD40–induced NO repress the activity of MMP9 and concomitantly increased the expression of E-cadherin and tissue inhibitor of metalloproteinase (TIMP) 1 in an orthotopic model of renal cell carcinoma. NO attenuated 12-O-tetradecanoylphorbol 13-acetate (TPA) induction of MMP-9 by inhibiting protein Kinase C (PKC) in breast cancer. Transfection of iNOS induces apoptosis and suppresses tumour progression and metastasis in both ectopic and orthotopic xenograft mouse models of pancreatic cancer. The anti-cancer activity of Rhus coriaria has been demonstrated by its attenuation of NFκB, STAT3, and NO pathways that suppress cell migration and invasion and induce the cell cycle arrest and cell death in triple negative breast cancer (MDA-MB-231) cells. Tumour growth and metastasis was decreased in iNOS transfected B88 oral squamous carcinoma cells in both in vivo and in vitro settings. In contrast, the iNOS null fibrosarcoma cell line (KX-dw1, KX-dw4, and KX-dw7) and M5076 murine ovarian sarcoma cell lines injected into iNOS(¯/¯) mice showed more tumourigenicity and lung metastasis as compared to iNOS(+/+) counterparts. Treatment of TGF-β1-induced alveolar cells with DETA/NO (NO-donor) reduced EMT while treatment with L-NAME (NOS inhibitor) caused a spontaneous increase in EMT.

Promigratory effects of NO have also been reported. NO inhibits the aggregation of tumour cells and platelets in the microcirculation via cGMP-dependent mechanisms. NO activates EGFR and Src via S-nitrosation, leading to activation of β-catenin signalling in ER-negative and basal-like breast cancer. Furthermore, treatment with an NO-donor (DETA/NO) of ER-negative breast cancer cells induced EMT by decreasing expression of E-cadherin and a concomitant increase in vimentin and β-catenin. Spontaneously developing tumours in a murine mammary adenocarcinoma (C3H/HeJ) model showed heterogeneous expression of eNOS within the primary tumours and homogeneous eNOS positivity in their metastatic counterparts, suggesting NO mediated tumour progression and metastasis. Furthermore, higher expression of eNOS was observed in clones derived from a spontaneous mammary tumour C3L5 (highly metastatic) than C10 cells (weakly metastatic). However, treatment of C3L5 and C10 bearing tumour mice with an eNOS inhibitor (L-NAME) reduced invasiveness of both cell lines. B16-BL6 murine melanoma cells injected in syngeneic iNOS(+/+) mice produced more and larger metastases than their iNOS(¯/¯) counterparts. A threefold higher invasive potential was observed in HRT-18 cells constitutively expressing iNOS compared to non-iNOS expressing HT-29 cells using Matrigel invasion assay. Treatment of HT-29 cells with an NO-donor (DETA/NO, 50 nM) and inflammatory cytokines (IFN-γ and IL-1α) in an independent experiment showed a significant increase in invasiveness, whereas the invasiveness of HRT-18 and HT29 were partially inhibited by the NOS inhibitor 1400W. NO produced by iNOS enhanced the activity of MMP-9, resulting in angiogenesis, invasion, and metastasis in hepatocellular carcinoma. MMP-9 and/or uPAR activated by iNOS in glioma cells induced cell migration via their interaction with α9β1 integrin.

3.7. Immunomodulatory Effects

NO-mediated communication between tumours and the microenvironment can have a major impact on tumour biology. NO regulates apoptosis and survival of different immune cells (dendritic cells, mast cells, NK cells, and phagocytes such as macrophages, monocytes, Kupffer cells, microglia, eosinophils, and neutrophils) and other cells in the tumour microenvironment (epithelial cells, endothelial cells, vascular smooth muscle cells, Schwann cells, fibroblasts, keratinocytes, chondrocytes, hepatocytes, and mesangial cells). Induction of the innate immune response is initiated by activation of classical macrophages (M1) that secrete proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), proteases (e.g., MMP-9), and NO/RNS. Increased production of NO activates downstream signalling pathways that perform a critical role in the cytotoxic activity of immune cells against tumour cells. Similarly, the tumouricidal and pathogen eradication capacity of natural killer (NK) cells is regulated partly by their NO synthesising ability.

Even though macrophage-generated NO participates in cytotoxic and antitumour activity in the tumour microenvironment, NO is recognised as an immunosuppressive mediator that helps to create a barrier against the anti-tumour immune responses. NO-mediated immunosuppression has been demonstrated in human prostate carcinoma by its inhibition of arginase 1 (ARG1) in T cells and diminished antitumoural activity of tumour-infiltrating lymphocytes (TILs) resulting from tyrosine nitration. NO production may also lead to S-nitrosation of the chemokine CCL2 and inhibit the infiltration of T cells into the tumour through its ability to retain myeloid-derived suppressor cells (MDSCs). NO produced by MDSCs reduces endothelial expression of E-selectin in human squamous cell carcinomas, thus preventing the recruitment T-cells into tumours. The autocrine effects of iNOS in IL-17 secreting γδT cells plays a key role in the recruitment of MDSCs and activation of regulatory T (Treg) cells that induce the pro-tumourigenic physiognomy in melanoma. MDSC-derived NO inhibits antigen presentation to CD4+ helper T cells by dendritic cells (DCs) and nitrates STAT1 to impair of T-cell JAK/STAT signalling proteins necessary for various T-cell functions in melanoma tumour models. MDSC-derived NO has also been demonstrated to lead to nitration of the tyrosine residues of NK cell-specific proteins, impairing Fc receptor-mediated NK cell functions and therapeutic responses to monoclonal antibodies. Thus, NO exerts widely different impacts on the recruitment of myeloid and lymphoid-derived cells, thereby restricting the capacity of iNOS inhibition to restore immune function. In considering the role of NO in immunomodulation it is also important to note that species specific differences exist in NO fluxes from iNOS, which may impact the roles of iNOS in immune cell modulation by different cell types including mesenchymal stromal cells and macrophages. A more detailed review on the role of NO in macrophages and cancer is provided in.

4. NO-Mediated Strategies for Cancer Treatment

Due to the biphasic nature of NO signalling, modulation of NO biosynthesis and exogenous delivery have been purported as therapeutic strategies against cancer. While tumour cell derived NO is rarely capable of killing cancer cells, it can be exploited to achieve clinical benefit by sensitising tumour cells to chemo, immune- and radiotoxicities. Thus, releasing adequate amounts of NO at the cancer site by iNOS over-expression (gene therapy) or administration of NO-donors (such as organic nitrates, N-nitrosamines, S-nitrozotiols, nitrozimines, and metal–NO complexes) or administration of NO-donor linked non-steroidal anti-inflammatory drugs (NO-NSAIDs) represent attractive novel strategies for cancer treatment.

Many NO-donors have been generated that can be defined on the basis of their utilisation in cancer therapeutics. Organic nitrates such as glyceryltrinitrate (GTN) and isosorbidedinitrate (ISDN) are the oldest class of NO-donors. The anticancer properties of GTN have been demonstrated in both in vitro and in vivo murine melanoma models. GTN has also being used with vinorelbine/cisplatin as a chemosensitiser in human NSCLC. Due to the high affinity of NO for metals, metal-NO complexes including sodium nitroprusside (SNP) have been synthesised as anti-neoplastic compounds with activity in prostate, gastric and cervical cancer cells, and radiosensitisating ability in pancreatic and glioma cancer cells. S-nitrosothiols (RSNO) such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) are also used as anti-cancerous agents. Both SNAP and GSNO are relatively stable and have anti-neoplastic impacts in different malignancies. In fact, both compounds have been shown to act significantly in the radiosensitisation of different tumours. Sydnonimines are another class of NO-releasing mesoionic heterocyclic compounds that yield superoxide-generated peroxynitrite during their decomposition. 3-morpholinosydnonimine (SIN-1) has been the most widely investigated compounds of this class. SIN-1 causes single-stranded DNA breaks, stimulates protein nitration and suppresses mitochondrial respiration. Diazeniumdiolates (also called NONOates) are a class of NO-donors that have gained tremendous attention due to release of controlled fluxes of NO in both in vitro and in vivo applications. Such compounds have a common structure, R1R2NN(O)=NOR3, in which all three R groups can be varied to create a large series of interesting compounds.

Depending on the identity of the amine group, such compounds have half-lives ranging from 2 s to 20 h. These compounds have been widely tested as chemo- and radiosensitising drugs/agents to produce synergistic results with traditional cancer therapeutics. Hybrid NO-donor drugs have been developed by hybridising the NO-donor(s) with an anticancer drug/agent/fragment, ideally by a cancer-specific linker of synergistic function that reduces the adverse effects caused by either component alone. This rationale triggered the development of various NO-linked NSAIDs (NO-NSAIDs) in which the NO-releasing moiety was linked by covalent bonding to standard NSAIDs such as salicylic acid, aspirin, indomethacin, sulindac or ibuprofen. The NSAID-linker-NO-donor adduct is often separated by non-specific esterase activity, which results in synergistic COX-inhibition and NO-production. Various NO-NSAIDs are identified as NCX-# (i.e., NCX-976, NCX-4016, NCX-4040, and NCX-4215) and are currently being explored in cancer therapy.

In the case of tumours that overexpress iNOS leading to increased metastasis and poor patient outcomes, an approach utilising iNOS inhibitors may be appropriate. This is particularly relevant to cancers where iNOS promotes poor outcomes. iNOS is known to be associated with poor outcome in ER negative breast cancer, and the rarer triple negative breast cancer (TNBC). In a nude mouse model of human triple negative breast cancer with the cell line MDA-MB-231, the iNOS inhibitor aminoguanidine inhibited tumour growth and metastasis to the brain. This was accompanied by the repression of tumour promoting factors including S100A8, IL-6, and IFN-γ. Dual inhibition of iNOS (aminoguanidine) and COX2 (aspirin), which predict poor outcome in ER negative breast cancer, further repressed MDA-MB-231 tumour growth via repression of TRAF2 dependent signalling. Metaplastic breast cancer is a stromal dominant rare form of breast cancer, with a high association with the triple negative breast cancer subtype. Elevated iNOS and ribosomal protein L39 was associated with poor survival in metaplastic tumours, while the pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA) repressed metaplastic murine model tumour growth. Further exploration of iNOS in triple negative breast cancer patients revealed that iNOS activates EGFR and MEK-ERK signalling, leading to increased risk of distant metastasis and poor outcome. Dávila-González et al. investigated the ability of t L-NMMA to repress TNBC patient-derived xenografts tumour growth, and found that combination therapy with docetaxel ameliorated tumour growth via activation of ATF4-CHOP mediated apoptosis. Similarly iNOS inhibition reduced tumour growth in a murine model of Kras and p53 mutation-positive non-small cell lung cancer, and enhanced the efficacy of carboplatin based chemotherapy. The NOS inhibitor N-nitro-l-arginine repressed tumour growth in a murine pancreatic cancer model. When given in combination with a VEGFR2 inhibitor it further repressed tumour growth and vascular perfusion. Similar effects have been observed in pancreatic cancer with eNOS specific inhibitors and pan-NOS inhibitors.

5. Conclusions

The evidence summarised in this review demonstrates that NO plays a crucial role in the regulation of tumour growth, angiogenesis, and metastasis. The role of NO in tumour biology depends on its source and thus its spatial, temporal, and multi-level dose control. Taken together, this determines a pro- or anti-tumourigenic response mediated by a cGMP-dependent process and/or post-translational protein alterations. Given that NO has the ability to initiate or regulate virtually all the hallmarks of cancer, this suggests that NO may be a master regulator of tumourigenesis and tumour promotion. This presents an opportunity to disrupt aberrant NO signalling at various points along the carcinogenesis pathway and thus simultaneously target multiple hallmarks of cancer. Thus, the findings in both in vitro and in vivo experiments related to NO have now made a strong argument that NO alone or in combination with anticancer drugs may provide new routes for the treatment of a variety of human malignancies. Although these findings have yet to be fully translated to the clinic, clinical trials of NO-donors and iNOS inhibitors are currently underway. The application of NO-based anticancer drugs certainly merits further investigation to harness and unlock its potential as a novel therapeutic strategy.

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  56. 56.

    Shapiro R., Dubelman S., Feinberg A.M., Crain P.F., McCloskey J.A. Isolation and identification of cross-linked nucleosides from nitrous acid treated deoxyribonucleic acid. Am. Chem. Soc. 1977;99:302-303.

    Not in our library10.1021/ja00443a080

  57. 57.

    Liu R.H., Baldwin B., Tennant B.C., Hotchkiss J.H. Elevated formation of nitrate and N-nitrosodimethylamine in woodchucks (Marmota monax) associated with chronic woodchuck hepatitis virus infection. Cancer Res. 1991;51:3925-3929.

    Not in our library

  58. 58.

    Forrester K., Ambs S., Lupold S.E., Kapust R.B., Spillare E.A., Weinberg W.C., Felley-Bosco E., Wang X.W., Geller D.A., Tzeng E., et al. Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. Proc. Natl. Acad. Sci. USA. 1996;93:2442-2447.

    Not in our library10.1073/pnas.93.6.2442

  59. 59.

    Wink D.A., Laval J. The Fpg protein, a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo. Carcinogenesis. 1994;15:2125-2129.

    Not in our library10.1093/carcin/15.10.2125

  60. 60.

    Radi R., Beckman J.S., Bush K.M., Freeman B.A. Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Arch Biochem. Biophys. 1991;288:481-487.

    Not in our library10.1016/0003-9861(91)90224-7

  61. 61.

    Wink D.A., Kasprzak K.S., Maragos C.M., Elespuru R.K., Misra M., Dunams T.M., Cebula T.A., Koch W.H., Andrews A.W., Allen J.S., et al. DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science. 1991;254:1001-1003.

    Not in our library10.1126/science.1948068

  62. 62.

    Nguyen T., Brunson D., Crespi C.L., Penman B.W., Wishnok J.S., Tannenbaum S.R. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc. Natl. Acad. Sci. USA. 1992;89:3030-3034.

    Not in our library10.1073/pnas.89.7.3030

  63. 63.

    deRojas-Walker T., Tamir S., Ji H., Wishnok J.S., Tannenbaum S.R. Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA. Chem. Res. Toxicol. 1995;8:473-477.

    Not in our library10.1021/tx00045a020

  64. 64.

    Harris C.C., Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N. Engl. J. Med. 1993;329:1318-1327.

    Not in our library10.1056/nejm199310283291807

  65. 65.

    Tornaletti S., Pfeifer G.P. Complete and tissue-independent methylation of CpG sites in the p53 gene: Implications for mutations in human cancers. Oncogene. 1995;10:1493-1499.

    Not in our library

  66. 66.

    Greenblatt M.S., Bennett W.P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855-4878.

    Not in our library

  67. 67.

    Routledge M.N., Wink D.A., Keefer L.K., Dipple A. DNA sequence changes induced by two nitric oxide donor drugs in the supF assay. Chem. Res. Toxicol. 1994;7:628-632.

    Not in our library10.1021/tx00041a007

  68. 68.

    Marnett L.J., Burcham P.C. Endogenous DNA adducts: Potential and paradox. Chem. Res. Toxicol. 1993;6:771-785.

    Not in our library10.1021/tx00036a005

  69. 69.

    Wu D., Hu Q., Zhu D. An Update on Hydrogen Sulfide and Nitric Oxide Interactions in the Cardiovascular System. Oxidative Med. Cell. Longev. 2018;2018:4579140.

    Not in our library10.1155/2018/4579140

  70. 70.

    Baker P.R., Schopfer F.J., O’Donnell V.B., Freeman B.A. Convergence of nitric oxide and lipid signaling: Anti-inflammatory nitro-fatty acids. Free Radic. Biol. Med. 2009;46:989-1003.

    Not in our library10.1016/j.freeradbiomed.2008.11.021

  71. 71.

    Hogg N., Kalyanaraman B. Nitric oxide and low-density lipoprotein oxidation. Free. Radic. Res. 1998;28:593-600.

    Not in our library10.3109/10715769809065815

  72. 72.

    Faulkner K.M., Liochev S.I., Fridovich I. Stable Mn(III) porphyrins mimic superoxide dismutase in vitro and substitute for it in vivo. J. Biol. Chem. 1994;269:23471-23476.

    Not in our library

  73. 73.

    Yermilov V., Rubio J., Becchi M., Friesen M.D., Pignatelli B., Ohshima H. Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis. 1995;16:2045-2050.

    Not in our library10.1093/carcin/16.9.2045

  74. 74.

    Juedes M.J., Wogan G.N. Peroxynitrite-induced mutation spectra of pSP189 following replication in bacteria and in human cells. Mutat. Res. 1996;349:51-61.

    Not in our library10.1016/0027-5107(95)00152-2

  75. 75.

    Ramezanian M.S., Padmaja S., Koppenol W.H. Nitration and hydroxylation of phenolic compounds by peroxynitrite. Chem. Res. Toxicol. 1996;9:232-240.

    Not in our library10.1021/tx950135w

  76. 76.

    Epe B., Ballmaier D., Roussyn I., Briviba K., Sies H. DNA damage by peroxynitrite characterized with DNA repair enzymes. Nucleic Acids Res. 1996;24:4105-4110.

    Not in our library10.1093/nar/24.21.4105

  77. 77.

    Chong Y.C., Heppner G.H., Paul L.A., Fulton A.M. Macrophage-mediated induction of DNA strand breaks in target tumor cells. Cancer Res. 1989;49:6652-6657.

    Not in our library

  78. 78.

    Eastman A., Barry M.A. The origins of DNA breaks: A consequence of DNA damage, DNA repair, or apoptosis? Cancer Investig. 1992;10:229-240.

    Not in our library10.3109/07357909209032765

  79. 79.

    Ross W.E. DNA topoisomerases as targets for cancer therapy. Biochem. Pharmacol. 1985;34:4191-4195.

    Not in our library10.1016/0006-2952(85)90273-4

  80. 80.

    Broillet M.C., Firestein S. Direct activation of the olfactory cyclic nucleotide-gated channel through modification of sulfhydryl groups by NO compounds. Neuron. 1996;16:377-385.

    Not in our library10.1016/s0896-6273(00)80055-0

  81. 81.

    Lander H.M., Ogiste J.S., Teng K.K., Novogrodsky A. p21ras as a common signaling target of reactive free radicals and cellular redox stress. J. Biol. Chem. 1995;270:21195-21198.

    Not in our library10.1074/jbc.270.36.21195

  82. 82.

    Caselli A., Camici G., Manao G., Moneti G., Pazzagli L., Cappugi G., Ramponi G. Nitric oxide causes inactivation of the low molecular weight phosphotyrosine protein phosphatase. J. Biol. Chem. 1994;269:24878-24882.

    Not in our library

  83. 83.

    Kim S.F. The role of nitric oxide in prostaglandin biology; update. Nitric Oxide. 2011;25:255-264.

    Not in our library10.1016/j.niox.2011.07.002

  84. 84.

    Messmer U.K., Brune B. Nitric oxide (NO) in apoptotic versus necrotic RAW 264.7 macrophage cell death: The role of NO-donor exposure, NAD+ content, and p53 accumulation. Arch. Biochem. Biophys. 1996;327:1-10.

    Not in our library10.1006/abbi.1996.0085

  85. 85.

    Muhl H., Sandau K., Brune B., Briner V.A., Pfeilschifter J. Nitric oxide donors induce apoptosis in glomerular mesangial cells, epithelial cells and endothelial cells. Eur. J. Pharmacol. 1996;317:137-149.

    Not in our library10.1016/s0014-2999(96)00701-7

  86. 86.

    Marnett L.J. Generation of mutagens during arachidonic acid metabolism. Cancer Metastasis Rev. 1994;13:303-308.

    Not in our library10.1007/bf00666100

  87. 87.

    Laval F., Wink D.A. Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase. Carcinogenesis. 1994;15:443-447.

    Not in our library10.1093/carcin/15.3.443

  88. 88.

    Mota M.B.S., Carvalho M.A., Monteiro A.N.A., Mesquita R.D. DNA damage response and repair in perspective: Aedes aegypti, Drosophila melanogaster and Homo sapiens. Parasites Vectors. 2019;12:533.

    Not in our library10.1186/s13071-019-3792-1

  89. 89.

    Hoeijmakers J.H. DNA damage, aging, and cancer. N. Engl. J. Med. 2009;361:1475-1485.

    Not in our library10.1056/nejmra0804615

  90. 90.

    Diderich K., Alanazi M., Hoeijmakers J.H. Premature aging and cancer in nucleotide excision repair-disorders. DNA Repair. 2011;10:772-780.

    Not in our library10.1016/j.dnarep.2011.04.025

  91. 91.

    Kennedy R.D., D’Andrea A.D. DNA repair pathways in clinical practice: Lessons from pediatric cancer susceptibility syndromes. J. Clin. Oncol. 2006;24:3799-3808.

    Not in our library10.1200/jco.2005.05.4171

  92. 92.

    Rolig R.L., McKinnon P.J. Linking DNA damage and neurodegeneration. Trends Neurosci. 2000;23:417-424.

    Not in our library10.1016/s0166-2236(00)01625-8

  93. 93.

    Akbari M., Krokan H.E. Cytotoxicity and mutagenicity of endogenous DNA base lesions as potential cause of human aging. Mech. Ageing Dev. 2008;129:353-365.

    Not in our library10.1016/j.mad.2008.01.007

  94. 94.

    Negrini S., Gorgoulis V.G., Halazonetis T.D. Genomic instability—An evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 2010;11:220-228.

    Not in our library10.1038/nrm2858

  95. 95.

    Olaussen K.A., Dunant A., Fouret P., Brambilla E., Andre F., Haddad V., Taranchon E., Filipits M., Pirker R., Popper H.H., et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N. Engl. J. Med. 2006;355:983-991.

    Not in our library10.1056/nejmoa060570

  96. 96.

    de Boer J., Hoeijmakers J.H. Nucleotide excision repair and human syndromes. Carcinogenesis. 2000;21:453-460.

    Not in our library10.1093/carcin/21.3.453

  97. 97.

    Scharer O.D. Nucleotide excision repair in eukaryotes. Cold Spring Harb. Perspect. Biol. 2013;5:a012609.

    Not in our library10.1101/cshperspect.a012609

  98. 98.

    Karikkineth A.C., Scheibye-Knudsen M., Fivenson E., Croteau D.L., Bohr V.A. Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res. Rev. 2017;33:3-17.

    Not in our library10.1016/j.arr.2016.08.002

  99. 99.

    Lehmann A.R. DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie. 2003;85:1101-1111.

    Not in our library10.1016/j.biochi.2003.09.010

  100. 100.

    Bensenouci S., Louhibi L., De Verneuil H., Mahmoudi K., Saidi-Mehtar N. Diagnosis of Xeroderma Pigmentosum Groups A and C by Detection of Two Prevalent Mutations in West Algerian Population: A Rapid Genotyping Tool for the Frequent XPC Mutation c.1643_1644delTG. BioMed Res. Int. 2016;2016:2180946.

    Not in our library10.1155/2016/2180946

  101. 101.

    Chien Y.H., Bau D.T., Jan K.Y. Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic. Biol. Med. 2004;36:1011-1017.

    Not in our library10.1016/j.freeradbiomed.2004.01.011

  102. 102.

    Qu J., Liu G.H., Huang B., Chen C. Nitric oxide controls nuclear export of APE1/Ref-1 through S-nitrosation of cysteines 93 and 310. Nucleic Acids Res. 2007;35:2522-2532.

    Not in our library10.1093/nar/gkl1163

  103. 103.

    Carter R.J., Parsons J.L. Base Excision Repair, a Pathway Regulated by Posttranslational Modifications. Mol. Cell. Biol. 2016;36:1426-1437.

    Not in our library10.1128/mcb.00030-16

  104. 104.

    Robertson K.A., Bullock H.A., Xu Y., Tritt R., Zimmerman E., Ulbright T.M., Foster R.S., Einhorn L.H., Kelley M.R. Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Res. 2001;61:2220-2225.

    Not in our library

  105. 105.

    Albertella M.R., Lau A., O’Connor M.J. The overexpression of specialized DNA polymerases in cancer. DNA Repair. 2005;4:583-593.

    Not in our library10.1016/j.dnarep.2005.01.005

  106. 106.

    Lord C.J., Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr. Opin. Pharmacol. 2008;8:363-369.

    Not in our library10.1016/j.coph.2008.06.016

  107. 107.

    Liu L., Gerson S.L. Therapeutic impact of methoxyamine: Blocking repair of abasic sites in the base excision repair pathway. Curr. Opin. Investig. Drugs. 2004;5:623-627.

    Not in our library

  108. 108.

    Jaiswal M., LaRusso N.F., Shapiro R.A., Billiar T.R., Gores G.J. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology. 2001;120:190-199.

    Not in our library10.1053/gast.2001.20875

  109. 109.

    Nakano T., Katafuchi A., Shimizu R., Terato H., Suzuki T., Tauchi H., Makino K., Skorvaga M., Van Houten B., Ide H. Repair activity of base and nucleotide excision repair enzymes for guanine lesions induced by nitrosative stress. Nucleic Acids Res. 2005;33:2181-2191.

    Not in our library10.1093/nar/gki513

  110. 110.

    Mutamba J.T., Svilar D., Prasongtanakij S., Wang X.H., Lin Y.C., Dedon P.C., Sobol R.W., Engelward B.P. XRCC1 and base excision repair balance in response to nitric oxide. DNA Repair (Amst). 2011;10:1282-1293.

    Not in our library10.1016/j.dnarep.2011.10.008

  111. 111.

    Parrish M.C., Chaim I.A., Nagel Z.D., Tannenbaum S.R., Samson L.D., Engelward B.P. Nitric oxide induced S-nitrosation causes base excision repair imbalance. DNA Repair (Amst). 2018;68:25-33.

    Not in our library10.1016/j.dnarep.2018.04.008

  112. 112.

    Li G.M. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18:85-98.

    Not in our library10.1038/cr.2007.115

  113. 113.

    Iyama T., Wilson D.M. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair. 2013;12:620-636.

    Not in our library10.1016/j.dnarep.2013.04.015

  114. 114.

    Guillotin D., Martin S.A. Exploiting DNA mismatch repair deficiency as a therapeutic strategy. Exp. Cell Res. 2014;329:110-115.

    Not in our library10.1016/j.yexcr.2014.07.004

  115. 115.

    Heinen C.D. Mismatch repair defects and Lynch syndrome: The role of the basic scientist in the battle against cancer. DNA Repair (Amst.). 2016;38:127-134.

    Not in our library10.1016/j.dnarep.2015.11.025

  116. 116.

    Belcheva A., Green B., Weiss A., Streutker C., Martin A. Elevated incidence of polyp formation in APC(Min/(+))Msh2(-)/(-) mice is independent of nitric oxide-induced DNA mutations. PLoS ONE. 2013;8:e65204.

    Not in our library10.1371/journal.pone.0065204

  117. 117.

    Her J., Bunting S.F. How cells ensure correct repair of DNA double-strand breaks. J. Biol. Chem. 2018;293:10502-10511.

    Not in our library10.1074/jbc.tm118.000371

  118. 118.

    Rodgers K., McVey M. Error-Prone Repair of DNA Double-Strand Breaks. J. Cell. Physiol. 2016;231:15-24.

    Not in our library10.1002/jcp.25053

  119. 119.

    Sun J., Lee K.J., Davis A.J., Chen D.J. Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J. Biol. Chem. 2012;287:4936-4945.

    Not in our library10.1074/jbc.m111.306167

  120. 120.

    Mahaney B.L., Meek K., Lees-Miller S.P. Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem. J. 2009;417:639-650.

    Not in our library10.1042/bj20080413

  121. 121.

    Jalal S., Earley J.N., Turchi J.J. DNA repair: From genome maintenance to biomarker and therapeutic target. Clin. Cancer Res. 2011;17:6973-6984.

    Not in our library10.1158/1078-0432.ccr-11-0761

  122. 122.

    Murray J.E., van der Burg M., IJspeert H., Carroll P., Wu Q., Ochi T., Leitch A., Miller E.S., Kysela B., Jawad A., et al. Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am. J. Hum. Genet. 2015;96:412-424.

    Not in our library10.1016/j.ajhg.2015.01.013

  123. 123.

    Xu W., Liu L., Smith G.C., Charles L.G. Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents. Nat. Cell Biol. 2000;2:339-345.

    Not in our library10.1038/35014028

  124. 124.

    Li X., Heyer W.D. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res. 2008;18:99-113.

    Not in our library10.1038/cr.2008.1

  125. 125.
    Homology and enzymatic requirements of microhomology-dependent alternative end joining · 2015
    No notice
  126. 126.

    Chen H., Lisby M., Symington L.S. RPA coordinates DNA end resection and prevents formation of DNA hairpins. Mol. Cell. 2013;50:589-600.

    Not in our library10.1016/j.molcel.2013.04.032

  127. 127.

    Mazin A.V., Bornarth C.J., Solinger J.A., Heyer W.D., Kowalczykowski S.C. Rad54 protein is targeted to pairing loci by the Rad51 nucleoprotein filament. Mol. Cell. 2000;6:583-592.

    Not in our library10.1016/s1097-2765(00)00057-5

  128. 128.

    Krejci L., Altmannova V., Spirek M., Zhao X. Homologous recombination and its regulation. Nucleic Acids Res. 2012;40:5795-5818.

    Not in our library10.1093/nar/gks270

  129. 129.

    Yakovlev V.A. Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability. Cancer Res. 2013;73:706-715.

    Not in our library10.1158/0008-5472.can-12-3270

  130. 130.

    Mujoo K., Pandita R.K., Tiwari A., Charaka V., Chakraborty S., Singh D.K., Hambarde S., Hittelman W.N., Horikoshi N., Hunt C.R., et al. Differentiation of Human Induced Pluripotent or Embryonic Stem Cells Decreases the DNA Damage Repair by Homologous Recombination. Stem Cell Rep. 2017;9:1660-1674.

    Not in our library10.1016/j.stemcr.2017.10.002

  131. 131.

    Aqil M., Elseth K.M., Vesper B.J., Deliu Z., Aydogan B., Xue J., Radosevich J.A. Part I-mechanism of adaptation: High nitric oxide adapted A549 cells show enhanced DNA damage response and activation of antiapoptotic pathways. Tumour Biol. 2014;35:2403-2415.

    Not in our library10.1007/s13277-013-1318-6

  132. 132.
    Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword · 2016
    No notice
  133. 133.

    Venclovas C., Thelen M.P. Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Res. 2000;28:2481-2493.

    Not in our library10.1093/nar/28.13.2481

  134. 134.

    Bell S.P., Dutta A. DNA replication in eukaryotic cells. Ann. Rev. bioChem. 2002;71:333-374.

    Not in our library10.1146/annurev.biochem.71.110601.135425

  135. 135.

    Zhao H., Piwnica-Worms H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol. Cell. Biol. 2001;21:4129-4139.

    Not in our library10.1128/mcb.21.13.4129-4139.2001

  136. 136.

    Shibata A., Barton O., Noon A.T., Dahm K., Deckbar D., Goodarzi A.A., Lobrich M., Jeggo P.A. Role of ATM and the damage response mediator proteins 53BP1 and MDC1 in the maintenance of G(2)/M checkpoint arrest. Mol. Cell. Biol. 2010;30:3371-3383.

    Not in our library10.1128/mcb.01644-09

  137. 137.

    Boutros R., Lobjois V., Ducommun B. CDC25 phosphatases in cancer cells: Key players? Good targets? Nat. Rev. Cancer. 2007;7:495-507.

    Not in our library10.1038/nrc2169

  138. 138.

    Dai Y., Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin. Cancer Res. 2010;16:376-383.

    Not in our library10.1158/1078-0432.ccr-09-1029

  139. 139.

    Buscemi G., Perego P., Carenini N., Nakanishi M., Chessa L., Chen J., Khanna K., Delia D. Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene. 2004;23:7691-7700.

    Not in our library10.1038/sj.onc.1207986

  140. 140.

    Mailand N., Falck J., Lukas C., Syljuasen R.G., Welcker M., Bartek J., Lukas J. Rapid destruction of human Cdc25A in response to DNA damage. Science. 2000;288:1425-1429.

    Not in our library10.1126/science.288.5470.1425

  141. 141.
    CHK2 kinase in the DNA damage response and beyond · 2014
    No notice
  142. 142.

    Ahn J., Urist M., Prives C. Questioning the role of checkpoint kinase 2 in the p53 DNA damage response. J. Biol. Chem. 2003;278:20480-20489.

    Not in our library10.1074/jbc.m213185200

  143. 143.
    Cyclin D activates the Rb tumor suppressor by mono-phosphorylation · 2014
    No notice
  144. 144.

    Falck J., Petrini J.H., Williams B.R., Lukas J., Bartek J. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat. Genet. 2002;30:290-294.

    Not in our library10.1038/ng845

  145. 145.

    Xiao Z., Chen Z., Gunasekera A.H., Sowin T.J., Rosenberg S.H., Fesik S., Zhang H. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J. Biol. Chem. 2003;278:21767-21773.

    Not in our library10.1074/jbc.m300229200

  146. 146.

    Lim D.S., Kim S.T., Xu B., Maser R.S., Lin J., Petrini J.H., Kastan M.B. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature. 2000;404:613-617.

    Not in our library10.1038/35007091

  147. 147.

    Wilson K.A., Stern D.F. NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway. Cell Cycle. 2008;7:3584-3594.

    Not in our library10.4161/cc.7.22.7102

  148. 148.

    Hofseth L.J., Saito S., Hussain S.P., Espey M.G., Miranda K.M., Araki Y., Jhappan C., Higashimoto Y., He P., Linke S.P., et al. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc. Natl. Acad. Sci. USA. 2003;100:143-148.

    Not in our library10.1073/pnas.0237083100

  149. 149.

    Wang X., Zalcenstein A., Oren M. Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation. Cell Death Differ. 2003;10:468-476.

    Not in our library10.1038/sj.cdd.4401181

  150. 150.

    de Gooijer M.C., van den Top A., Bockaj I., Beijnen J.H., Wurdinger T., van Tellingen O. The G2 checkpoint-a node-based molecular switch. FEBS Open Bio. 2017;7:439-455.

    Not in our library10.1002/2211-5463.12206

  151. 151.

    Taylor W.R., Stark G.R. Regulation of the G2/M transition by p53. Oncogene. 2001;20:1803-1815.

    Not in our library10.1038/sj.onc.1204252

  152. 152.

    Thornton T.M., Rincon M. Non-classical p38 map kinase functions: Cell cycle checkpoints and survival. Int. J. Biol. Sci. 2009;5:44-51.

    Not in our library10.7150/ijbs.5.44

  153. 153.

    Liu Z., Li G., Gou Y., Xiao D., Luo G., Saavedra J.E., Liu J., Wang H. JS-K, a nitric oxide prodrug, induces DNA damage and apoptosis in HBV-positive hepatocellular carcinoma HepG2.2.15 cell. Biomed. Pharmacother. 2017;92:989-997.

    Not in our library10.1016/j.biopha.2017.05.141

  154. 154.

    Kiziltepe T., Hideshima T., Ishitsuka K., Ocio E.M., Raje N., Catley L., Li C.Q., Trudel L.J., Yasui H., Vallet S., et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood. 2007;110:709-718.

    Not in our library10.1182/blood-2006-10-052845

  155. 155.

    Gao L., Williams J.L. Nitric oxide-donating aspirin induces G2/M phase cell cycle arrest in human cancer cells by regulating phase transition proteins. Int. J. Oncol. 2012;41:325-330.

    Not in our library10.3892/ijo.2012.1455

  156. 156.

    Nakanishi M., Shimada M., Niida H. Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci. 2006;97:984-989.

    Not in our library10.1111/j.1349-7006.2006.00289.x

  157. 157.

    Vasa M., Breitschopf K., Zeiher A.M., Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ. Res. 2000;87:540-542.

    Not in our library10.1161/01.res.87.7.540

  158. 158.

    Grasselli A., Nanni S., Colussi C., Aiello A., Benvenuti V., Ragone G., Moretti F., Sacchi A., Bacchetti S., Gaetano C., et al. Estrogen receptor-alpha and endothelial nitric oxide synthase nuclear complex regulates transcription of human telomerase. Circ. Res. 2008;103:34-42.

    Not in our library10.1161/circresaha.107.169037

  159. 159.

    Kim P.K., Zamora R., Petrosko P., Billiar T.R. The regulatory role of nitric oxide in apoptosis. Int. Immunopharmacol. 2001;1:1421-1441.

    Not in our library10.1016/s1567-5769(01)00088-1

  160. 160.

    Johlfs M.G., Fiscus R.R. Protein kinase G type-Ialpha phosphorylates the apoptosis-regulating protein Bad at serine 155 and protects against apoptosis in N1E-115 cells. Neurochem. Int. 2010;56:546-553.

    Not in our library10.1016/j.neuint.2009.12.017

  161. 161.

    Wang X., Chen M., Zhou J., Zhang X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (Review). Int. J. Oncol. 2014;45:18-30.

    Not in our library10.3892/ijo.2014.2399

  162. 162.

    Azad N., Vallyathan V., Wang L., Tantishaiyakul V., Stehlik C., Leonard S.S., Rojanasakul Y. S-nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation. A novel antiapoptotic mechanism that suppresses apoptosis. J. Biol. Chem. 2006;281:34124-34134.

    Not in our library10.1074/jbc.m602551200

  163. 163.

    Blaise G.A., Gauvin D., Gangal M., Authier S. Nitric oxide, cell signaling and cell death. Toxicology. 2005;208:177-192.

    Not in our library10.1016/j.tox.2004.11.032

  164. 164.

    Pilz R.B., Casteel D.E. Regulation of gene expression by cyclic GMP. Circ. Res. 2003;93:1034-1046.

    Not in our library10.1161/01.res.0000103311.52853.48

  165. 165.

    Ashkenazi A., Dixit V.M. Death receptors: Signaling and modulation. Science. 1998;281:1305-1308.

    Not in our library10.1126/science.281.5381.1305

  166. 166.

    Garban H.J., Bonavida B. Nitric oxide sensitizes ovarian tumor cells to Fas-induced apoptosis. Gynecol. Oncol. 1999;73:257-264.

    Not in our library10.1006/gyno.1999.5374

  167. 167.

    Biton S., Ashkenazi A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell. 2011;145:92-103.

    Not in our library10.1016/j.cell.2011.02.023

  168. 168.

    Brune B. Nitric oxide: NO apoptosis or turning it ON? Cell Death Differ. 2003;10:864-869.

    Not in our library10.1038/sj.cdd.4401261

  169. 169.

    Chae H.J., So H.S., Chae S.W., Park J.S., Kim M.S., Oh J.M., Chung Y.T., Yang S.H., Jeong E.T., Kim H.M., et al. Sodium nitroprusside induces apoptosis of H9C2 cardiac muscle cells in a c-Jun N-terminal kinase-dependent manner. Int. Immunopharmacol. 2001;1:967-978.

    Not in our library10.1016/s1567-5769(01)00033-9

  170. 170.

    Kim S.J., Ju J.W., Oh C.D., Yoon Y.M., Song W.K., Kim J.H., Yoo Y.J., Bang O.S., Kang S.S., Chun J.S. ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J. Biol. Chem. 2002;277:1332-1339.

    Not in our library10.1074/jbc.m107231200

  171. 171.

    Edilova M.I., Abdul-Sater A.A., Watts T.H. TRAF1 Signaling in Human Health and Disease. Front. Immunol. 2018;9:2969.

    Not in our library10.3389/fimmu.2018.02969

  172. 172.

    Holmgren L., O’Reilly M.S., Folkman J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1995;1:149-153.

    Not in our library10.1038/nm0295-149

  173. 173.

    Kazerounian S., Lawler J. Integration of pro- and anti-angiogenic signals by endothelial cells. J. Cell Commun. Signal. 2018;12:171-179.

    Not in our library10.1007/s12079-017-0433-3

  174. 174.

    Morbidelli L., Donnini S., Ziche M. Role of nitric oxide in the modulation of angiogenesis. Curr. Pharm. Des. 2003;9:521-530.

    Not in our library10.2174/1381612033391405

  175. 175.

    Wink D.A., Vodovotz Y., Laval J., Laval F., Dewhirst M.W., Mitchell J.B. The multifaceted roles of nitric oxide in cancer. Carcinogenesis. 1998;19:711-721.

    Not in our library10.1093/carcin/19.5.711

  176. 176.

    Forsythe J.A., Jiang B.H., Iyer N.V., Agani F., Leung S.W., Koos R.D., Semenza G.L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 1996;16:4604-4613.

    Not in our library10.1128/mcb.16.9.4604

  177. 177.

    Zhou J., Schmid T., Brune B. HIF-1alpha and p53 as targets of NO in affecting cell proliferation, death and adaptation. Curr. Mol. Med. 2004;4:741-751.

    Not in our library10.2174/1566524043359926

  178. 178.

    Ying L., Hofseth L.J. An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res. 2007;67:1407-1410.

    Not in our library10.1158/0008-5472.can-06-2149

  179. 179.

    Fulton D., Gratton J.P., McCabe T.J., Fontana J., Fujio Y., Walsh K., Franke T.F., Papapetropoulos A., Sessa W.C. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399:597-601.

    Not in our library10.1038/21218

  180. 180.

    Chen J.X., Meyrick B. Hypoxia increases Hsp90 binding to eNOS via PI3K-Akt in porcine coronary artery endothelium. Lab. Investig. 2004;84:182-190.

    Not in our library10.1038/labinvest.3700027

  181. 181.

    Brouet A., Sonveaux P., Dessy C., Balligand J.L., Feron O. Hsp90 ensures the transition from the early Ca2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells. J. Biol. Chem. 2001;276:32663-32669.

    Not in our library10.1074/jbc.m101371200

  182. 182.

    Isenberg J.S., Ridnour L.A., Perruccio E.M., Espey M.G., Wink D.A., Roberts D.D. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc. Natl. Acad. Sci. USA. 2005;102:13141-13146.

    Not in our library10.1073/pnas.0502977102

  183. 183.

    Ridnour L.A., Isenberg J.S., Espey M.G., Thomas D.D., Roberts D.D., Wink D.A. Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc. Natl. Acad. Sci. USA. 2005;102:13147-13152.

    Not in our library10.1073/pnas.0502979102

  184. 184.

    Namkoong S., Lee S.J., Kim C.K., Kim Y.M., Chung H.T., Lee H., Han J.A., Ha K.S., Kwon Y.G., Kim Y.M. Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Exp. Mol. Med. 2005;37:588-600.

    Not in our library10.1038/emm.2005.72

  185. 185.

    Ziche M., Morbidelli L., Masini E., Amerini S., Granger H.J., Maggi C.A., Geppetti P., Ledda F. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J. Clin. Investig. 1994;94:2036-2044.

    Not in our library10.1172/jci117557

  186. 186.

    Talmadge J.E., Fidler I.J. AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 2010;70:5649-5669.

    Not in our library10.1158/0008-5472.can-10-1040

  187. 187.

    Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674.

    Not in our library10.1016/j.cell.2011.02.013

  188. 188.

    Gos M., Miloszewska J., Przybyszewska M. Epithelial-mesenchymal transition in cancer progression. Postep. Biochem. 2009;55:121-128.

    Not in our library

  189. 189.

    Banyard J., Bielenberg D.R. The role of EMT and MET in cancer dissemination. Connect. Tissue Res. 2015;56:403-413.

    Not in our library10.3109/03008207.2015.1060970

  190. 190.

    Baritaki S., Huerta-Yepez S., Sahakyan A., Karagiannides I., Bakirtzi K., Jazirehi A., Bonavida B. Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: Inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP. Cell Cycle. 2010;9:4931-4940.

    Not in our library10.4161/cc.9.24.14229

  191. 191.

    Bonavida B., Baritaki S. Inhibition of Epithelial-to-Mesenchymal Transition (EMT) in Cancer by Nitric Oxide: Pivotal Roles of Nitrosylation of NF-kappaB, YY1 and Snail. Forum Immunopathol. Dis. Ther. 2012;3:125-133.

    Not in our library10.1615/forumimmundisther.2012006065

  192. 192.

    Hickok J.R., Sahni S., Mikhed Y., Bonini M.G., Thomas D.D. Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: Role of chelatable iron. J. Biol. Chem. 2011;286:41413-41424.

    Not in our library10.1074/jbc.m111.287052

  193. 193.

    Vyas-Read S., Shaul P.W., Yuhanna I.S., Willis B.C. Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2007;293:L212-L221.

    Not in our library10.1152/ajplung.00475.2006

  194. 194.

    Jespersen C., Doller A., Akool E.S., Bachmann M., Muller R., Gutwein P., Muhl H., Pfeilschifter J., Eberhardt W. Molecular mechanisms of nitric oxide-dependent inhibition of TPA-induced matrix metalloproteinase-9 (MMP-9) in MCF-7 cells. J. Cell Physiol. 2009;219:276-287.

    Not in our library10.1002/jcp.21658

  195. 195.

    Gonzalez-Avila G., Sommer B., Garcia-Hernandez A.A., Ramos C. Matrix Metalloproteinases’ Role in Tumor Microenvironment. Adv. Exp. Med. Biol. 2020;1245:97-131.

    Not in our library10.1007/978-3-030-40146-7_5

  196. 196.

    Singh T., Chaudhary S.C., Kapur P., Weng Z., Elmets C.A., Kopelovich L., Athar M. Nitric oxide donor exisulind is an effective inhibitor of murine photocarcinogenesis. Photochem. Photobiol. 2012;88:1141-1148.

    Not in our library10.1111/j.1751-1097.2012.01093.x

  197. 197.

    Ray J.M., Stetler-Stevenson W.G. The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. Eur. Respir. J. 1994;7:2062-2072.

    Not in our library

  198. 198.

    Akool E.S., Kleinert H., Hamada F.M., Abdelwahab M.H., Forstermann U., Pfeilschifter J., Eberhardt W. Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol. Cell. Biol. 2003;23:4901-4916.

    Not in our library10.1128/mcb.23.14.4901-4916.2003

  199. 199.

    Weiss J.M., Ridnour L.A., Back T., Hussain S.P., He P., Maciag A.E., Keefer L.K., Murphy W.J., Harris C.C., Wink D.A., et al. Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. J. Exp. Med. 2010;207:2455-2467.

    Not in our library10.1084/jem.20100670

  200. 200.

    Le X., Wei D., Huang S., Lancaster J.R., Xie K. Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. Proc. Natl. Acad. Sci. USA. 2005;102:8758-8763.

    Not in our library10.1073/pnas.0409581102

  201. 201.

    El Hasasna H., Saleh A., Al Samri H., Athamneh K., Attoub S., Arafat K., Benhalilou N., Alyan S., Viallet J., Al Dhaheri Y., et al. Rhus coriaria suppresses angiogenesis, metastasis and tumor growth of breast cancer through inhibition of STAT3, NFkappaB and nitric oxide pathways. Sci. Rep. 2016;6:21144.

    Not in our library10.1038/srep21144

  202. 202.

    Harada K., Supriatno, Kawaguchi S., Tomitaro O., Yoshida H., Sato M. Overexpression of iNOS gene suppresses the tumorigenicity and metastasis of oral cancer cells. In Vivo. 2004;18:449-455.

    Not in our library

  203. 203.

    Wei D., Richardson E.L., Zhu K., Wang L., Le X., He Y., Huang S., Xie K. Direct demonstration of negative regulation of tumor growth and metastasis by host-inducible nitric oxide synthase. Cancer Res. 2003;63:3855-3859.

    Not in our library

  204. 204.

    Shi Q., Xiong Q., Wang B., Le X., Khan N.A., Xie K. Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. Cancer Res. 2000;60:2579-2583.

    Not in our library

  205. 205.

    Irwin C., Roberts W., Naseem K.M. Nitric oxide inhibits platelet adhesion to collagen through cGMP-dependent and independent mechanisms: The potential role for S-nitrosylation. Platelets. 2009;20:478-486.

    Not in our library10.3109/09537100903159375

  206. 206.

    Switzer C.H., Glynn S.A., Cheng R.Y., Ridnour L.A., Green J.E., Ambs S., Wink D.A. S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer. Mol. Cancer Res. MCR. 2012;10:1203-1215.

    Not in our library10.1158/1541-7786.mcr-12-0124

  207. 207.

    Jadeski L.C., Lala P.K. Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am. J. Pathol. 1999;155:1381-1390.

    Not in our library10.1016/s0002-9440(10)65240-6

  208. 208.

    Orucevic A., Bechberger J., Green A.M., Shapiro R.A., Billiar T.R., Lala P.K. Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int. J. Cancer. 1999;81:889-896.

    Not in our library10.1002/(sici)1097-0215(19990611)81:6<889::aid-ijc9>3.0.co;2-2

  209. 209.

    Siegert A., Rosenberg C., Schmitt W.D., Denkert C., Hauptmann S. Nitric oxide of human colorectal adenocarcinoma cell lines promotes tumour cell invasion. Br. J. Cancer. 2002;86:1310-1315.

    Not in our library10.1038/sj.bjc.6600224

  210. 210.

    Sun M.H., Han X.C., Jia M.K., Jiang W.D., Wang M., Zhang H., Han G., Jiang Y. Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma. World J. Gastroenterol. 2005;11:5931-5937.

    Not in our library10.3748/wjg.v11.i38.5931

  211. 211.

    Veeravalli K.K., Rao J.S. MMP-9 and uPAR regulated glioma cell migration. Cell Adhes. Migr. 2012;6:509-512.

    Not in our library10.4161/cam.21673

  212. 212.

    Bogdan C. Nitric oxide and the immune response. Nat. Immunol. 2001;2:907-916.

    Not in our library10.1038/ni1001-907

  213. 213.

    Coleman J.W. Nitric oxide in immunity and inflammation. Int. Immunopharmacol. 2001;1:1397-1406.

    Not in our library10.1016/s1567-5769(01)00086-8

  214. 214.

    Wink D.A., Hines H.B., Cheng R.Y., Switzer C.H., Flores-Santana W., Vitek M.P., Ridnour L.A., Colton C.A. Nitric oxide and redox mechanisms in the immune response. J. Leukoc. Biol. 2011;89:873-891.

    Not in our library10.1189/jlb.1010550

  215. 215.
    Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities · 2019
    No notice
  216. 216.

    Bogdan C. Nitric oxide synthase in innate and adaptive immunity: An update. Trends Immunol. 2015;36:161-178.

    Not in our library10.1016/j.it.2015.01.003

  217. 217.

    Bronte V., Kasic T., Gri G., Gallana K., Borsellino G., Marigo I., Battistini L., Iafrate M., Prayer-Galetti T., Pagano F., et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 2005;201:1257-1268.

    Not in our library10.1084/jem.20042028

  218. 218.

    Molon B., Ugel S., Del Pozzo F., Soldani C., Zilio S., Avella D., De Palma A., Mauri P., Monegal A., Rescigno M., et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 2011;208:1949-1962.

    Not in our library10.1084/jem.20101956

  219. 219.

    Gehad A.E., Lichtman M.K., Schmults C.D., Teague J.E., Calarese A.W., Jiang Y., Watanabe R., Clark R.A. Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas. J. Investig. Dermatol. 2012;132:2642-2651.

    Not in our library10.1038/jid.2012.190

  220. 220.

    Nagaraj S., Gupta K., Pisarev V., Kinarsky L., Sherman S., Kang L., Herber D.L., Schneck J., Gabrilovich D.I. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 2007;13:828-835.

    Not in our library10.1038/nm1609

  221. 221.

    Jayaraman P., Parikh F., Lopez-Rivera E., Hailemichael Y., Clark A., Ma G., Cannan D., Ramacher M., Kato M., Overwijk W.W., et al. Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J. Immunol. 2012;188:5365-5376.

    Not in our library10.4049/jimmunol.1103553

  222. 222.

    Douguet L., Bod L., Lengagne R., Labarthe L., Kato M., Avril M.F., Prevost-Blondel A. Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of gammadelta17 T cells in melanoma. Oncoimmunology. 2016;5:e1208878.

    Not in our library10.1080/2162402x.2016.1208878

  223. 223.

    Markowitz J., Wang J., Vangundy Z., You J., Yildiz V., Yu L., Foote I.P., Branson O.E., Stiff A.R., Brooks T.R., et al. Nitric oxide mediated inhibition of antigen presentation from DCs to CD4(+) T cells in cancer and measurement of STAT1 nitration. Sci. Rep. 2017;7:15424.

    Not in our library10.1038/s41598-017-14970-0

  224. 224.

    Stiff A., Trikha P., Mundy-Bosse B., McMichael E., Mace T.A., Benner B., Kendra K., Campbell A., Gautam S., Abood D., et al. Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function. Clin. Cancer Res. 2018;24:1891-1904.

    Not in our library10.1158/1078-0432.ccr-17-0691

  225. 225.

    Jayaraman P., Alfarano M.G., Svider P.F., Parikh F., Lu G., Kidwai S., Xiong H., Sikora A.G. iNOS expression in CD4+ T cells limits Treg induction by repressing TGFbeta1: Combined iNOS inhibition and Treg depletion unmask endogenous antitumor immunity. Clin. Cancer Res. 2014;20:6439-6451.

    Not in our library10.1158/1078-0432.ccr-13-3409

  226. 226.

    Su J., Chen X., Huang Y., Li W., Li J., Cao K., Cao G., Zhang L., Li F., Roberts A.I., et al. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species. Cell Death Differ. 2014;21:388-396.

    Not in our library10.1038/cdd.2013.149

  227. 227.

    Chinnadurai R., Sands J., Rajan D., Liu X., Arafat D., Das R., Anania F.A., Gibson G., Kisseleva T., Galipeau J. Molecular Genetic and Immune Functional Responses Distinguish Bone Marrow Mesenchymal Stromal Cells from Hepatic Stellate Cells. Stem Cells. 2019;37:1075-1082.

    Not in our library10.1002/stem.3028

  228. 228.

    Hoos M.D., Vitek M.P., Ridnour L.A., Wilson J., Jansen M., Everhart A., Wink D.A., Colton C.A. The impact of human and mouse differences in NOS2 gene expression on the brain’s redox and immune environment. Mol. Neurodegener. 2014;9:50.

    Not in our library10.1186/1750-1326-9-50

  229. 229.

    Ryan A.E., Burke A.J., Giles F.J., Sullivan F.J., Glynn S.A., Bonavida B. Mechanisms of Nitric Oxide-Dependent Regulation of Tumor Invasion and Metastasis. Nitric Oxide and Cancer: Pathogenesis and Therapy. 2015;49-63.

    Not in our library

  230. 230.

    Ridnour L.A., Thomas D.D., Donzelli S., Espey M.G., Roberts D.D., Wink D.A., Isenberg J.S. The biphasic nature of nitric oxide responses in tumor biology. Antioxid. Redox Signal. 2006;8:1329-1337.

    Not in our library10.1089/ars.2006.8.1329

  231. 231.

    Bonavida B., Garban H. Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics. Redox Biol. 2015;6:486-494.

    Not in our library10.1016/j.redox.2015.08.013

  232. 232.

    Huang Z., Fu J., Zhang Y. Nitric Oxide Donor-Based Cancer Therapy: Advances and Prospects. J. Med. Chem. 2017;60:7617-7635.

    Not in our library10.1021/acs.jmedchem.6b01672

  233. 233.

    Sukhatme V., Bouche G., Meheus L., Sukhatme V.P., Pantziarka P. Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent. Ecancermedicalscience. 2015;9:568.

    Not in our library10.3332/ecancer.2015.568

  234. 234.

    Huerta S., Chilka S., Bonavida B. Nitric oxide donors: Novel cancer therapeutics (review). Int. J. Oncol. 2008;33:909-927.

    Not in our library10.3892/ijo_00000079

  235. 235.

    Park I.C., Woo S.H., Park M.J., Lee H.C., Lee S.J., Hong Y.J., Lee S.H., Hong S.I., Rhee C.H. Ionizing radiation and nitric oxide donor sensitize Fas-induced apoptosis via up-regulation of Fas in human cervical cancer cells. Oncol. Rep. 2003;10:629-633.

    Not in our library

  236. 236.

    Mitchell J.B., Wink D.A., DeGraff W., Gamson J., Keefer L.K., Krishna M.C. Hypoxic mammalian cell radiosensitization by nitric oxide. Cancer Res. 1993;53:5845-5848.

    Not in our library

  237. 237.

    Wang P.G., Xian M., Tang X., Wu X., Wen Z., Cai T., Janczuk A.J. Nitric oxide donors: Chemical activities and biological applications. Chem. Rev. 2002;102:1091-1134.

    Not in our library10.1021/cr000040l

  238. 238.

    Inoue S., Kawanishi S. Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett. 1995;371:86-88.

    Not in our library10.1016/0014-5793(95)00873-8

  239. 239.

    Keefer L.K. Progress toward clinical application of the nitric oxide-releasing diazeniumdiolates. Annu. Rev. Pharmacol. Toxicol. 2003;43:585-607.

    Not in our library10.1146/annurev.pharmtox.43.100901.135831

  240. 240.

    Thatcher G.R., Nicolescu A.C., Bennett B.M., Toader V. Nitrates and NO release: Contemporary aspects in biological and medicinal chemistry. Free Radic. Biol. Med. 2004;37:1122-1143.

    Not in our library10.1016/j.freeradbiomed.2004.06.013

  241. 241.

    Glynn S.A., Boersma B.J., Dorsey T.H., Yi M., Yfantis H.G., Ridnour L.A., Martin D.N., Switzer C.H., Hudson R.S., Wink D.A., et al. Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J. Clin. Investig. 2010;120:3843-3854.

    Not in our library10.1172/jci42059

  242. 242.

    Walsh E.M., Keane M.M., Wink D.A., Callagy G., Glynn S.A. Review of Triple Negative Breast Cancer and the Impact of Inducible Nitric Oxide Synthase on Tumor Biology and Patient Outcomes. Crit. Rev. Oncog. 2016;21:333-351.

    Not in our library10.1615/critrevoncog.2017021307

  243. 243.

    Heinecke J.L., Ridnour L.A., Cheng R.Y., Switzer C.H., Lizardo M.M., Khanna C., Glynn S.A., Hussain S.P., Young H.A., Ambs S., et al. Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proc. Natl. Acad. Sci. USA. 2014;111:6323-6328.

    Not in our library10.1073/pnas.1401799111

  244. 244.

    Basudhar D., Glynn S.A., Greer M., Somasundaram V., No J.H., Scheiblin D.A., Garrido P., Heinz W.F., Ryan A.E., Weiss J.M., et al. Coexpression of NOS2 and COX2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer. Proc. Natl. Acad. Sci. USA. 2017;114:13030-13035.

    Not in our library10.1073/pnas.1709119114

  245. 245.

    Dave B., Gonzalez D.D., Liu Z.B., Li X., Wong H., Granados S., Ezzedine N.E., Sieglaff D.H., Ensor J.E., Miller K.D., et al. Role of RPL39 in Metaplastic Breast Cancer. J. Natl. Cancer Inst. 2017;109:djw292.

    Not in our library10.1093/jnci/djw292

  246. 246.

    Garrido P., Shalaby A., Walsh E.M., Keane N., Webber M., Keane M.M., Sullivan F.J., Kerin M.J., Callagy G., Ryan A.E., et al. Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. Oncotarget. 2017;8:80568-80588.

    Not in our library10.18632/oncotarget.19631

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    Davila-Gonzalez D., Choi D.S., Rosato R.R., Granados-Principal S.M., Kuhn J.G., Li W.F., Qian W., Chen W., Kozielski A.J., Wong H., et al. Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer. Clin. Cancer Res. 2018;24:1152-1162.

    Not in our library10.1158/1078-0432.ccr-17-1437

  248. 248.

    Pershing N.L., Yang C.F.J., Xu M., Counter C.M. Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell lung cancer. Oncotarget. 2016;7:42385-42392.

    Not in our library10.18632/oncotarget.9874

  249. 249.

    Camp E.R., Yang A., Liu W., Fan F., Somcio R., Hicklin D.J., Ellis L.M. Roles of nitric oxide synthase inhibition and vascular endothelial growth factor receptor-2 inhibition on vascular morphology and function in an in vivo model of pancreatic cancer. Clin. Cancer Res. 2006;12:2628-2633.

    Not in our library10.1158/1078-0432.ccr-05-2257

  250. 250.

    Lampson B.L., Kendall S.D., Ancrile B.B., Morrison M.M., Shealy M.J., Barrientos K.S., Crowe M.S., Kashatus D.F., White R.R., Gurley S.B., et al. Targeting eNOS in pancreatic cancer. Cancer Res. 2012;72:4472-4482.

    Not in our library10.1158/0008-5472.can-12-0057

  251. 251.

    Fujita M., Somasundaram V., Basudhar D., Cheng R.Y.S., Ridnour L.A., Higuchi H., Imadome K., No J.H., Bharadwaj G., Wink D.A. Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype. Redox Biol. 2019;22:101158.

    Not in our library10.1016/j.redox.2019.101158

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