Tejaswini P. ReddySharon A. Glynn snd, Timothy R. Billiar czncer, David A. WinkJenny C. Chang; Targeting Nitric Oxide: Say Adn to Metastasis. Clin Cancer Res 15 Ooxide ; 29 anf : — Black pepper extract for anti-aging review caner the influence of nitric prrvention NO canecr tumor pdevention and cancer metastasis, as well as promising preclinical studies that evaluated Preventiion inhibitors Pomegranate seeds nutrition anticancer therapies.
Lastly, we highlight the ad and outstanding challenges of using NOS inhibitors in the clinical setting. Cancer metastasis and Nitric oxide and cancer prevention resistance are Nitric oxide and cancer prevention fundamental causes of mortality from Nitirc tumors 1.
Vancer oxide NO within the TME has gained interest Nitrid its prevvention on tumor progression, metastasis, and cancerr resistance. Various studies have revealed that NO can both promote and inhibit tumor progression and metastasis 3—8. Therefore, it is warranted to Energy-boosting smoothie recipes the nuanced influence NO plays Nitrc cancer metastasis Antioxidant enzymes in disease prevention response to therapy.
This review summarizes pxide current knowledge of the roles of NO in tumor RMR and aging and cancer metastasis. We also discuss the adn of targeting Nitruc isoforms lxide augment the cance of systemic and targeted therapies for Nitric oxide and cancer prevention treatment.
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Altered S-nitrosation is crucial for promoting malignant phenotypes, including metastasis, angiogenesis, cell ocide, antiapoptotic signaling, genomic instability, oxkde metabolic reprogramming Fig. Cancre influence of NO for preventiob therapy and cellular signaling.
Oxice, Intermediate—low concentrations of NO can pevention tumor growth and angiogenesis and have canncer effects. Inhibition of NO can be caancer Nitric oxide and cancer prevention Nitrlc benefit by sensitizing tumor Nitric oxide and cancer prevention to Nitirc anticancer therapies.
Inhibition of NO as an anticancer therapeutic has shown clinical benefit in cancers, such as chemorefractory TNBC, with minimal side effects. sGC, soluble guanylate cyclase; Prvention, extracellular signaling-regulated ane PI3K, phosphoinositide oxidde HIF, hypoxia-inducible Nitrjc EGFR, Artichoke-centric Mediterranean cuisine growth factor receptor; COX, Nitric oxide and cancer prevention, oxlde.
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NO, nitric oxide; iNOS, inducible ptevention oxide synthase; EMT, epithelial-to-mesenchymal transition; MET, mesenchymal-to-epithelial cancee NET, neutrophil extracellular preventioon MMP, matrix metalloproteinase; TIMP1, tissue rpevention of metalloproteinase; TME, tumor Nitricc VEGF, vascular endothelial oxise factor; Mo-MDSC, monocytic prrevention suppressor cells; G-MDSC, granulocyte-like myeloid-derived suppressor cells; eNOS, endothelial Nitric oxide and cancer prevention oxide synthase; CCL2, C—C motif chemokine lrevention 2; SNO, S-nitrosothiol.
Canceg production of NO and dysregulated S-nitrosation can Hair growth after pregnancy tumor initiation and metastasis prevfntion The small GTPase Nitric oxide and cancer prevention, one of the earliest described Cancr targets, preventikn nitrosylated at Prevenntion, resulting in enhanced Nitrid nucleotide exchange prevvention stimulation of downstream pathways such Niyric MAPK prevwntion Switzer and colleagues canecr that in Oxife -high estrogen receptor ER -negative breast tumors, a subset of upregulated genes have binding sites for the Ets transcription factor Knockdown of Ets inhibited NO-dependent expression of basal-like breast cancer markers P-cadherin, SA8, IL8, and αβ-crystallinattenuated NO-mediated matrix metalloprotease activity, and cancer cell invasion.
NO, at physiologically relevant concentrations, can activate tyrosine kinases epidermal growth factor receptor EGFR and Src via S-nitrosation in TNBC cell lines In these studies, TNBC cell lines were treated with NO donor DETANO to recapitulate NO concentration fluxes found within the TME.
NO treatment via DETANO also reduced cell—cell adhesion and enhanced migratory capacity via the epithelial-to-mesenchymal transition EMT program Furthermore, they validated that estrogens could synergistically work with NOS to enhance cell migration and proliferation.
Therefore, NO-mediated c-Src activation may be crucial for cancer cell dissemination. In human breast cancer cells, Ridnour and colleagues found that iNOS-associated Akt phosphorylation required functional tissue inhibitor matrix metalloproteinase 1 TIMP Specifically, TIMP1 protein nitration and its protein—protein interaction with CD63 were observed in breast cancer cells that underwent NO-induced Akt activation.
These findings suggest that breast tumors with elevated iNOS and TIMP1 expression exert their oncogenic function by Akt activation, leading to an aggressive phenotype Furthermore, iNOS expression is associated with worse overall survival in melanoma patients with intact PTEN expression in tumors, likely via iNOS-mediated stimulation of PI3K signaling.
These findings present plausible mechanisms of how NO and nitrosative stress conditions can modulate the activation of prosurvival signaling pathways. S-nitrosation can also influence the mechanical properties of cells, as found in a study using a non—small cell lung cancer NSCLC model Ezrin, a cross-linker protein localized between microfilaments and the plasma membrane, is involved in intracellular mechanical activation crucial for cancer cell motility.
Lung adenocarcinoma patients with tumors having high expression of iNOS or ezrin had lower overall survival than tumors with low ezrin or iNOS. Ezrin can be S-nitrosylated at the Cys site in in vitro and in vivo NSCLC models after exposure to NO.
The Cys site is a key site for ezrin S-nitrosation that contributes to enhanced NSCLC invasion and metastasis. Specifically, S-nitrosation increases ezrin tension modulated by microfilament forces and is positively correlated with cancer aggressiveness In salivary gland adenoid cystic carcinoma SACCthe enhanced expression of Ezrin along with iNOS, CC44v6, and Ki67 protein expression is correlated with tumor histologic patterns, SACC metastases, and poor clinical outcomes Studies within the past decade reported that NO signaling influences cancer stem cell CSC growth and tumorigenic functions 44— CSCs are a small subpopulation of pluripotent cells within solid and hematologic cancers 49, These cells are associated with cell proliferation, tumor development, and metastatic dissemination and possess the ability to self-renew Relative to non—stem-like cancer cells, CSCs are typically chemo- and radioresistant Resistant CSCs within the tumor may contribute to relapse and poor clinical response, despite these therapeutic modalities destroying a significant portion of the tumor bulk The TME is a key contributor of molecules e.
Preclinical and clinical TNBC studies show that targeting NO with NOS inhibitors may target resistant CSC populations, thereby augmenting the efficacy of chemotherapy 47, 52— These two gene signatures were predominantly found in residual tumor cells post-letrozole or docetaxel therapy and had a predominant expression of EMT genes Residual breast cancer stem cell BCSC populations that survive after conventional therapy may have mesenchymal features and self-renewal capacity.
Follow-up studies later revealed key genes responsible for BCSC survival and showed that their activities were mediated via NO signaling 47, Using the gene signature specific to BCSC from Creighton and colleagues, Dave and colleagues later discovered two key genes crucial for BCSC self-renewal capacity, MS formation, and lung metastases, ribosomal-like protein 39 RPL39 and myeloid-leukemia factor 2 MLF2 ; ref.
Targeting RPL39 and MLF2 genes with siRNAs reduced TNBC CSCs as assessed with mammosphere formation efficiency MSFE assay, flow cytometry, and limiting dilution assay.
The lower expression of RPL39 and MLF2 also reduced tumor growth in TNBC patient-derived xenograft PDX models, augmented the efficacy of chemotherapy, improved overall survival, and reduced lung metastasis.
Ingenuity Pathway Analysis found that NO signaling was the top pathway implicated in the RPL39 and MLF2 function regulation in BCSCs.
Mechanistic studies revealed that in an HIF1α-dependent manner, hypoxia induced the expression of RPL39 and MLF2 with a concomitant increase in iNOS in breast cancer cell lines. In an HIF1α-independent manner, NOS inhibition reduced the expression of downstream proteins of NOS [ soluble guanylate cyclase SCG and cyclic-GMP-dependent kinase-1].
Therefore, in an HIF1α-dependent manner, hypoxia transcriptionally activated RPL39 and MLF2leading to increased protein expression of iNOS and enhanced metastasis.
CSCs have been shown to reside in hypoxic regions in solid tumors. Their survival is likely dependent on hypoxia-mediated activation of iNOS, NO-mediated stabilization of HIF1α, and NO within the tumor microenvironment influencing breast cancer initiation and metastasis 60— Elevated endogenous mRNA and protein expression of iNOS in TNBC tumors is associated with a worse clinical prognosis Selective inhibition of iNOS via W inhibitor and pan-NOS [NG-monomethyl-L-arginine L-NMMA and NG-nitroarginine methyl ester L-NAME inhibitors] reduced TNBC cell proliferation, BCSC self-renewal, migration, and reduced the protein expression of crucial EMT transcription factors Zeb1, Snail, Slug, and Twist1lung metastases and tumor initiation in human TNBC cell line models These findings suggest that NOS inhibition may induce mesenchymal-to-epithelial transition in tumor cells, reducing metastatic capacity and rendering breast cancer cells more chemosensitive.
Besides BCSC populations, NO derived from iNOS is also involved in maintaining stem-like tumor cells from gliomas, hepatocellular carcinoma, and colon cancer 44, 48, Compared with normal neural progenitors and non-GSCs, GSCs depend on iNOS activity for maintenance and tumorigenicity.
Furthermore, elevated tumor expression of iNOS and decreased expression of CDA-1 is correlated with worse overall survival in human glioma patients A plausible, yet unexplored explanation for why CSCs depend on iNOS function for maintenance in comparison with non-stem-like cells may be due to differential regulation of its gene expression.
The NOS2 gene is differentially regulated in murine and human macrophages due to epigenetic modifications specifically enhanced CpG methylation proximal to the gene's transcription start site in human versus murine macrophages; ref.
Though there has been no definite investigation of this concept, it is plausible that the NOS2 gene may be epigenetically silenced in non-stem cancer cells in comparison with CSCs. Puglisi and colleagues showed that colon CSCs with high endogenous NO production have higher tumorigenic abilities than CSCs that produce low NO fractions Pharmacologic and genomic inhibition of iNOS significantly reduced colon CSCs tumorigenic capacity in vitro and in vivolikely due to reduced expression of genes involved in tumor initiation and CSC maintenance CD, β-catenin, Bmi-1, and NF-κB p NOS2 knockdown in colon CSCs led to enhanced biosynthesis of alkaline phosphatase after exposure to sodium butyrate, revealing that NOS expression modulates cellular differentiation.
Using a superficial colon tumor model, NOS2 knockdown blocked the growth of colon CSC-derived xenografts, suggesting that iNOS may be a potential therapeutic target in the treatment and management of colon cancer.
The Notch signaling pathway is a highly conserved signal transduction pathway crucial for CSC maintenance, self-renewal capacity, and metastasis Altered Notch signaling has been associated with self-renewal and metastasis in human breast and hepatocellular carcinoma HCC stem cells 67— iNOS is involved in driving the activation of Notch signaling and expression of target genes, such as Hes-1, in cancers such as cholangiocarcinoma and gliomas 70, An unbiased chemical screening study using a drosophila eye tumor model showed that activated PI3K signaling triggered immunosuppression and inflammation via aberrant NOS signaling, leading to enhanced Notch-mediated tumorigenesis iRhom2 interacts with an activated form of TACE, resulting in the translocation of TACE to the cell surface, cleavage of Notch-1, Notch intracellular domain NICD entering the nucleus, interacting with DNA-binding protein CSL to activate transcription of Notch target genes such as HES1 and Hey1 In patients with HCC, elevated expression of iNOS, NICD, and TACE was correlated with poor prognosis.
Table 1 summarizes the biological influence of inducible NOS and nitric oxide on cancer progression and metastasis in a range of solid tumors. The novel cancer gene ribosomal protein L39 RPL39 is responsible for stem cell self-renewal, treatment resistance, and lung metastases in TNBC.
Mechanistically, RPL39 increases iNOS-mediated NO production
: Nitric oxide and cancer prevention| International Journal of Analysis in Medicinal Chemistry | Preevention Matter Pages i-xxiii. Qnd expression in turn suppressed tumor cell migration Download all slides. Furthermore, they validated that estrogens could synergistically work with NOS to enhance cell migration and proliferation. Google Scholar. |
| Free Radical: Nitric Oxide in Cancer Therapy | Nat Oxidde Biol ; 2 — pylori -induced gastritis [ 72 ]. Parsonnet J, Friedman Nitric oxide and cancer prevention, Oremtreich N, Vogelman H: Preevntion for Cholesterol-lowering strategies cancer oxiee Nitric oxide and cancer prevention with CagA positive or CagA negative Helicobacter pylori infection. Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma. This review summarizes our current knowledge of the roles of NO in tumor progression and cancer metastasis. Wang K. |
| Nitric Oxide and Cancer: Pathogenesis and Therapy | When NO reacts with DOX superoxide, it forms peroxynitrate much quicker, which increases cancer cell death [12]. Several studies have utilized the prodrug delivery strategy and found success in inhibiting cancer growth [13, 14]. One major challenge in the medical treatment of cancer is multi-drug resistance MDR , which can occur when cancer drugs alter the chemical environment of the cancer cells, such as by changing the pH, thereby influencing the permeability of cancer cell membranes and making them less receptive to the drugs [15]. MDR is largely mediated by transmembrane efflux pump proteins, such as ATP-binding cassette ABC transporters and multidrug resistance-associated proteins MRP [15]. Hypoxia in tumor cells increases the expression of the efflux pumps [15] the focus of recent researches has been to deliver NO in conjunction with other cancer fighting drugs to study its secondary effects in cancer cells such as, its inhibition of the transmembrane efflux pumps. Nitric oxide has been found to be effective in deactivating transmembrane efflux pumps by conjugating with heme groups, those when bound with NO, assume an oxy conformation in the hypoxic environment of tumor cells, thereby deactivating the expression of the transmembrane efflux pumps [15]. Moreover, Nitric oxide has been recently investigated for its potential in combating the multi-drug resistance of certain cancers by inhibiting DNA repair and production of proteins in cancer cells, proving to be effective in multi-drug chemotherapy treatment [12]. In cancer radiotherapy, a challenge is that hypoxic cells, cancer cells with minimal levels of oxygen, in the tumors are minimally radiosensitive [16]. Studies have shown that NO is capable of radio sensitizing hypoxic cells by increasing their level of oxygenation through NO-mediated pathways that alter blood flow and increase intake of oxygen by the cell [17]. Studies have demonstrated that increasing the rate of nitric oxide production in cancer cells in conjunction with radiotherapy can lead to as much as 3. Nitric oxide and ionizing radiation have been shown to induce apoptotic cell death in conjunction with one another by phosphorylating p53 which induces the apoptotic pathway [19]. It was found in one study that treating colorectal cancer cells with NO donors led to a significant increase in the radiosensitivity of the cancer cells [18]. Recently, nanoparticle-based delivery systems have made the site-selective delivery of exogenous NO sources more effective to tumor cells. It has also shown to counteract the extremely indiscriminate toxic effects of NO and allow its cytotoxic effects be more focused on the target cancer cells [20]. In one study, nanoparticle platforms have shown to be superior to small molecule chemo sensitizers in that they allow cancer fighting drugs, such as NO, to accumulate within the body system by extending their blood circulation, improving their effectiveness and increasing successful, accurate tumor penetration rate [21]. It may also be an effective tool to counter MDR, as specifically demonstrated in a study with NO bound to BNN6 and enclosed in mPEG-PGLA copolymer nanoparticle. Results showed that the nanoparticles are capable of precisely delivering NO carriers to tumor cells and successfully initiating the NO-mediated reversal of MDR and radio sensitization in the tumor cells [12]. Figure 1: Effects of nitric oxide in cancer treatment: A Cancer cells treated with nitric oxide releasing nanoparticles platform and cells were irradiated with X-ray. NO production after X-ray exposure nitric oxide was labeled with labeling dye DAF-FM green. B Resulting NO production enhanced the radio sensitizing effects and increased the DNA damage red , cells stained with thidium Homodimer III EthD-III dye for DNA damage staining. C The merge image shows the localization of both signals in the cellular compartment, which shows the effects of nitric oxide in DNA damage for cancer treatment. During preliminary reach study, we tried to investigate how nitric oxide-based delivery systems play a significant role in the treatment of cancer. In this study we designed a nanoparticle-based platform for delivery of nitric oxide to the cellular compartment of cancer cells and to investigate their radio sensitizing properties after exposure to low dose of X-Ray radiation. We observed that nitric oxide slowly releases to the cellular compartment and also produces more free radicals like nitric oxide NO Fig-1, green chancel. After irradiation with the X-ray, it resulted in enhanced DNA damage of the cancer cells Fig- 1, red chancel and suppressed growth of the tumor, effectively due to radio sensitizing properties data not published. The most significant limitation of nitric oxide is that an accurate delivery method is needed for effective utilization. This is because NO, as a free radical, is extremely toxic to all cells, not just the targeted cancer cells. Therefore, most research has focused on developing effective delivery methods for NO, whether it is by delivering it conjugated with other drugs or through a nanomedicine platform. The concentration of NO delivered is also something that has to be finely tuned, since concentrations that are too low will actually promote the growth of cancer cells by increasing the rate of glycolysis [7]. In addition, despite many NO donors, such as organic nitrates, diasenium diolates, S-nitrosothiols, metal-NO complexes, and furoxans showing anti-cancer effects on certain types of cancer cells, it is difficult to apply treatment with NO donors because NO donors can have serious negative, toxic side effects if they are not accurately, site-specifically delivered and activated. Conclusion and Future Perspective Top. Nitric oxide is a gaseous free radical molecule that is produced in living cells by nitric oxide synthesis, which are produced in large amounts within cells that have become cancerous. NO can promote tumor growth in cancer, as angiogenesis, stimulated by NO, is essential for tumor growth. However, high concentrations of NO are extremely toxic to cancer cells and so tumor growth can also be repressed. Due to its toxicity to cancer cells, NO has been studied for its potential usage in the medicinal science for cancer treatment. It has been found that site-directed delivery of NO deactivates the protein efflux pumps causing multidrug resistance in cancer. NO is also effective in radio sensitizing the tumor cells by increasing the cell oxygen level, thereby increasing the effectiveness of radiotherapy. Furthermore, Nanoparticlebased delivery systems of NO have been developed to increase the cancer-fighting capabilities of NO by increasing the accuracy of delivery, mitigating negative side effects of NO, and increasing tumor penetration. NO has already been shown to overcome many of the problems faced by other cancer-fighting agents and treatment methods, such as MDR and hypoxia of cancer cells. The use of nanoparticle NO delivery systems might be an effective platform for site-directed delivery to increase delivery accuracy, tumor penetration, efficiency against MDR, and cancer killing efficiency. In future studies, nanoparticle-based NO delivery platforms will likely have a significant role in improving the effectiveness of radiation therapy for the treatment and management of many types of cancer. Acknowledgement Top. We would also like to thank all the research scientists who are working on making progress to alleviate serious burdens on human health such as cancer. We would like to thank Mr. Mohammad Racin for his help during the revision process. References Top. Sharma K, Chakrapani H. Site-directed delivery of nitric oxide to cancers. Nitric Oxide. The role of nitric oxide in tumour progression. Nature Reviews Cancer. The potential role of nitric oxide in halting cancer progression through chemoprevention. Journal of cancer prevention. Nitric oxide and cancer: a review. World journal of surgical oncology. Nitric oxide in cancer metastasis. Cancer letters. Nitric oxide and cell death in liver cancer cells. Nitric oxide is a positive regulator of the Warburg effect in ovarian cancer cells. Nitric oxide regulation of free radical—and enzyme-mediated lipid and lipoprotein oxidation. Arteriosclerosis thrombosis and vascular biology. Snyder CM, Shroff EH, Liu J, Chandel NS. Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members. PloS one. Mice were treated with NOS2 inhibitor amino guanidine, before and after inoculation. After 4 weeks, cells derived from the arising tumors were transplanted into normal mice. Cells derived from the amino guanidine-treated mice tumors transplanted 4 weeks later had a significantly reduced incidence of metastases compared with controls A study investigated the effect of NO scavengers, non-isoform-selective NOS inhibitors and NOS2 selective inhibitors, on the growth and vascularization of rat carcinomasarcoma. This would suggest that a complete inhibition of NO is required for antitumor effects, rather than NOS2 alone Overexpression of NO by human osteocalcin in PC3 xenografts yielded tumor growth delays of up to Extensive investigation has been carried out on the effects of NO on cancer biology. At first glance, the data appear conflicting and inconclusive. This has led to difficulty in deciphering its role in tumor biology. However, upon closer examination of the available literature, it becomes quickly apparent that these conflicting results are in reality due to the biphasic nature of NO-mediated cellular effects, which are dependent on NO concentration experienced by the cells, NO flux, the chemical redox environment and the duration of NO exposure 24 , Consequently, NO can have both pro- and antitumorigenic effects 23 , which in terms of its potential as a therapeutic target provides us with multiple options. In tumors that are not NO-dependent, it is likely that NO donors be cytotoxic to the tumor, as these cells are not adapted to a NO-rich environment, this may be particularly useful for radiosensitization. Although the role of NO on cellular proliferation, EMT, angiogenesis, apoptosis and radiotherapy is well understood, its role in epigenetic regulation of cancer is an emerging area of interest. Further research is needed to decipher its impact on epigenetic mechanisms including DNA methylation regulation, chromatin remodeling, modulation of miRNAs and also new emerging non-coding RNAs such as lncRNA, snoRNA and piRNA. In conclusion, the multifaceted nature of NO in tumor biology demonstrates its role as a master regulator of tumor progression, with the ability to regulate multiple cellular processes in a dynamic fashion. Ignarro L. Google Scholar. Gladwin M. et al. Mocellin S. Muntané J. World J. Aranda E. Knowles R. Alderton W. Förstermann U. Heart J. Noble M. Stuehr D. Singh S. 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Malaguarnera L. Cancer Metastasis Rev. Tarr J. Brown G. Marshall H. Kim M. Brüne B. Cell Death Differ. Kim J. Olson S. Pan X. Zhao H. Suschek C. Kim Y. Piplani H. Cancer Prev. Wang K. Oronsky B. A review. Liebmann J. Maxhimer J. Saleem W. Cancer Sci. Sonveaux P. Cardnell R. Mitchell J. Stewart G. Policastro L. Cancer Lett. Cook T. De Ridder M. Paradise W. Illi B. Arif M. Vecellio M. Sha Y. Yakovlev V. Cobbs C. Liver Physiol. Kjaer-Frifeldt S. Siemens D. Laschak M. BMC Cancer. Kozoni V. Acta Pharmacol. Rigas B. Trends Mol. Williams J. Rao C. Lampson B. Takaoka K. Oral Maxillofac. Okada F. Capuano G. BMC Immunol. Flitney F. Coulter J. Gene Med. McCarthy H. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Navbar Search Filter Carcinogenesis This issue Clinical Cytogenetics and Molecular Genetics Books Journals Oxford Academic Mobile Enter search term Search. Issues More Content Advance articles Editor's Choice Submit Author Guidelines Submission Site Open Access Purchase Alerts About About Carcinogenesis Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Dispatch Dates Journals on Oxford Academic Books on Oxford Academic. Issues More Content Advance articles Editor's Choice Submit Author Guidelines Submission Site Open Access Purchase Alerts About About Carcinogenesis Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Dispatch Dates Close Navbar Search Filter Carcinogenesis This issue Clinical Cytogenetics and Molecular Genetics Books Journals Oxford Academic Enter search term Search. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Journal Article. The yin and yang of nitric oxide in cancer progression. Burke , Amy J. Oxford Academic. Francis J. Sharon A. Revision received:. PDF Split View Views. Cite Cite Amy J. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter Carcinogenesis This issue Clinical Cytogenetics and Molecular Genetics Books Journals Oxford Academic Enter search term Search. Abstract Nitric oxide NO is a short-lived, pleiotropic molecule that affects numerous critical functions in the body. Table I. Cell type. NO modulation. Effect of NO on function. Proliferation Keratinocytes 0. jp1 and SN12PM6 Ad. Open in new tab. Open in new tab Download slide. diethylenetriamine nitric oxide adduct. endothelium-derived relaxation factor. epithelial—mesenchymal transition. extracellular signal-regulated kinase. Nω-nitro- l -arginine methylester. NG-nitro- l -arginine. S-nitroso-N-acetyl- dl -penicillamine. vascular endothelial growth factor. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. Google Scholar PubMed. OpenURL Placeholder Text. Google Scholar Crossref. Search ADS. Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Potentiometric analysis of the flavin cofactors of neuronal nitric oxide synthase. Mechanism of nitric oxide synthase regulation: electron transfer and interdomain interactions. Google Scholar Google Preview OpenURL Placeholder Text. Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nitrergic innervation of the normal gut and in motility disorders of childhood. Tayfun Uzbay. Google Scholar OpenURL Placeholder Text. Position in cell cycle controls the sensitivity of colon cancer cells to nitric oxide-dependent programmed cell death. NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA expression. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p Relationship between p53 mutations and inducible nitric oxide synthase expression in human colorectal cancer. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of cases. Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis. Regulation of interleukin-8 expression by nitric oxide in human pancreatic adenocarcinoma. Nitric oxide is a key component in inflammation-accelerated tumorigenesis. An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Candidate pathways linking inducible nitric oxide synthase to a basal-like transcription pattern and tumor progression in human breast cancer. Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. Biphasic effect of exogenous nitric oxide on proliferation and differentiation in skin derived keratinocytes but not fibroblasts. Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents. Cdk2 nitrosylation and loss of mitochondrial potential mediate NO-dependent biphasic effect on HL cell cycle. Nitric oxide stimulates PC12 cell proliferation via cGMP and inhibits at higher concentrations mainly via energy depletion. Nitric oxide inhibits gastric cancer cell growth through the modulation of the Akt pathway. Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line MDA-MB : potential role of cyclin D1. Nitric oxide control of proliferation in nerve cells and in tumor cells of nervous origin. Nitrosulindac NCX : a new nitric oxide-donating non-steroidal anti-inflammatory drug NO-NSAID , inhibits proliferation and induces apoptosis in human prostatic epithelial cell lines. Antiproliferative effect of nitrosulindac NCX , a new nitric oxide-donating non-steroidal anti-inflammatory drug, on human bladder carcinoma cell lines. The novel NO-donating compound GITNO inhibits in vivo growth of human prostate cancer cells and prevents murine immunoinflammatory hepatitis. In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells. Localization of nitric oxide synthase in human trophoblast cells: role of nitric oxide in trophoblast proliferation and differentiation. Keith Bechtel. Inhibitory effects of 17beta-estradiol and progesterone on ovarian carcinoma cell proliferation: a potential role for inducible nitric oxide synthase. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase Nitric oxide promotes proliferation and plasminogen activator production by coronary venular endothelium through endogenous bFGF. Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells. A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis. Tumor cell nitric oxide inhibits cell growth in vitro , but stimulates tumorigenesis and experimental lung metastasis in vivo. Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis. |
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