In the central nerve system, NO has a variety of biological functions including vasorelaxation and neurotransmision. Interestingly, nNOS has been detected in some oligodendroglioma and neuroblastoma cell lines, althouth further studies are needed to clarified the role of nNOS in tumour pathology While NO had been shown to have anti-tumour properties 10 , Jenkins et al 42 [] first reported the surprising finding that human carcinoma cells transfected with a murine iNOS cDNA cassette DLD-1 cells generating 20 pmol min-1 mg-1 NOS activity showed increased tumour growth, rather than decreased growth.

These results were supported by Ambs et al, who used recombinant iNOS expressing Calu-6 and HT human carcinoma cell lines containing mutant p53 43 to look at tumour growth.

The authors demonstrated that an NO-mediated up-regulation of VEGF corresponded with increased vascularisation in the xenograft tumours. Therefore it is possible that NO generated by NOS located either within the tumour or in the surrounding stroma may promote new blood vessel formation by up-regulating VEGF.

This neovasculaturization not only enhances the ability of the tumour to grow, but also increases its invasiveness and metastatic ability.

As NO is a free radical, it is a highly reactive molecule within biological systems, capable of interaction with other free radicals, molecular oxygen and heavy metals. The biological effects of NO can be mediated by the products of different NO metabolites.

For example, NO rapidly reacts intracellularly to form nitrite and nitrate, S-nitroso-thiols or peroxynitrate, and these metabolites are believed to play key roles in mediating many of the NO-associated genotoxic effects. These effects include DNA damage, which can be initiated by nitrosative deamination, DNA strand breakage or DNA modification One of the consequences of the NO- mediated DNA damage is to trigger p53 accumulation, which can induce apoptosis.

This is a possible process by which NO may induce death of tumour cells. Interestingly, it has been demonstrated that accumulation of p53 results ultimately in down-regulation of iNOS expression by inhibition of iNOS promoter activity Thus a negative feedback loop is formed between NO-generation and p53 accumulation, that may constitute part of a physiological mechanism, which responds to endogenously produced DNA damage due to NO.

Overall, this pmediated growth inhibition may be expected to provide a strong selection pressure for mutant p53 expression in tumor cells. In addition to p53, NO has also been shown to activate poly ADP-ribose polymerase PARP 48 and it has been proposed that this activation is due to DNA damage.

This damage may take the form of DNA strand breaks or nitrosative deamination of DNA bases when NO is generated at high concentrations. These high concentrations of NO have been reported for NMDA-mediated neurotoxicity as well as for tumouricidal and bactericidal activation of cells Another important DNA repair enzyme, DNA-dependent protein kinase DNA-PK , is also known to be essential for the maintenance of the structural integrity of the genome.

Recently, mammalian DNA-PKcs has been shown to be an essential component of the DNA double-strand repair pathway, as well as being crucial for V D J recombination, involved in the generation of immunoglobulin and T-cell diversity. Scid mice, which lack DNA-PKcs, show increased susceptibility to ionising radiation in addition to having impaired V D J recombination and arrested T- and B-cell development Interestingly, although DNA-PK activity cannot be up-regulated by strong doses of radiation, we found that NO can act a signal, increasing the activity of DNA-PK.

Importantly, we showed that this increase occurred by transcriptional up-regulation of DNA-PKcs expression and occurred under physiologically relevant ranges of NO concentrations Biologically, this NO-mediated increase in enzymatically active DNA-PK not only protected cells from the toxic effects of NO, but also provided cross-protection against clinically important DNA-damaging agents, such as X-ray radiation, adriamycin, bleomycin and cisplatin The NO-mediated increase in DNA-PKcs pathway not only plays an important role in tumour DNA repair 51 , but may also play an important role in other tissue damage processes which involve NO-mediated stress 52 , Given the fact that one of the major substrates of DNA-PKcs is p53 54 and DNA-PKcs itself is subjected to ADP-ribosylation by PARP, it is possible that NO-mediated DNA damage and repair could play a significant role in tumour development Fig 3.

NO-based therapeutics can be traced back for more than a centrury when Willaim Murell proposed the sublingual application of nitroglycerin as a remedy for angina pectoris From the time of discovery of the vasodilatory properties of the organic nitrates and nitrites, it took more than hundred years to elucidate their mode of action at the molecular level.

For example, it was not until that NO gas was identified both as the endogenous endothelium-derived relaxing factor 3 , 4 , 5 , and as being involved as a primary defence mechanism against tumour cells and intracellular microorganisms Several laboratories have demonstarted that NO-releasing agents can kill tumour cells, and as a consequence there have been attempts deliver NO to cells.

While NO-releasing drugs are under developement, an attractive alternative mechanism for delivery would be to transfer NOS- encoding cDNA sequences into cancer cells for gene therapy purposes. Several studies have shown that this approach may work. For example, using a mouse model it was demonstarted that transfection of K melanoma cells with an iNOS cDNA expression cassette suppressed tumourogenicity and abrogated metastasis Transfection of human renal carcinoma cells with a retroviral iNOS cassette showed similar results A problem with current approaches however is that constitutive expression of NOS can quickly result in death of the transfectant, shortening the time that NO can be generated, and potentially limiting the utility of the approach.

NOS transfectants often have to be cultured under conditions that reduce toxicity for example in the presence of a NOS inhibitor , and transfection attempts may result in cells that are capable of relatively low levels of NO-generation As discussed above, this may result in concentrations of NO that promote tumour growth rather than cell killing.

Another significant point is that NOS enzyme activity requires a panel of substrates and co-factors for full activity, and these may be missing from the target cell type. For example synthesis of the important co-factor tetrahydrobiopterin BH4 , requires transcriptional regulation of the rate- limiting enzyme GTP-cyclohydrolase, which may not be induced in all target cells Lastly, both retroviral and adenoviral vector maybe hazardous to the host and pose a major health and safety risk A potential strategy to overcome the problems associated with gene therapy is to use a cell-based approach.

Cell-based approaches utilise the delivery of recombinant cells rather than genes to the target site, with the advantage that the expression of the gene of interest can be optimised prior to delivery.

For example, we have recently shown the utility of two novel iNOS-expressing human cell lines that can generate high concentrations of NO following treatment with analogues of either the insect hormone ecdysone or tetracycline 50 , In order to make the NO- generating cells suitable for therapeutic delivery they have been encapsulated within a semipermeable alginate-poly-L-lysine membrane.

Encapsulated cells are protected from environmental stresses encountered in the host such as the host immune response and can be delivered to tumour site s in a nude mouse model 58 , Following delivery, high concentrations of NO and reactive nitrogen species can be generated by administration of the appropriate inducer.

Overall we believe that the cell-delivery approach addresses some of the shortcomings of competing strategies and has the potential to inhibit or kill many different types of tumours from various histological origins The discovery of the generation of NO by mammalian tissues and the elucidation of some of its biological roles in cancer has thrown new light onto many areas of tumour biology research.

Although initial findings suggested that the immune-cell generated NO is cytostatic or cytotoxic for tumour cells, later findings have shown that NO can also possess apparently contradictory activity leading to increased tumour growth. NO can contribute to tumour angiogenesis by upregulating VEGF and modulating tumour DNA repair mechanism s by up-regulating p53, PARP and DNA-PKcs.

Overall, we can safely say that NO is a 'Doubled-Edged Sword'in cancer. On the one hand, high concentrations of NO, for example, generated by activated macrophages may mediate cancer cell apoptosis and the inhibition of cancer growth.

On the other hand, at relatively low concentrations of NO, for example, at concentrations measurable in many different types of clinical cancer samples , tumour growth and proliferation is promoted. The regulation of tumour growth by NO represents an important new dimension in cancer research.

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Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents. Nat Cell Biol ; 2 — It can be recommended to all readers who are interested in the pathogenesis and therapy of cancer.

Benjamin Bonavida. Book Title : Nitric Oxide and Cancer: Pathogenesis and Therapy. Editors : Benjamin Bonavida. Publisher : Springer Cham. eBook Packages : Biomedical and Life Sciences , Biomedical and Life Sciences R0.

Copyright Information : Springer International Publishing Switzerland Hardcover ISBN : Published: 01 June Softcover ISBN : Published: 09 October eBook ISBN : Published: 12 May Edition Number : 1. Number of Pages : XXIII, Policies and ethics.

Skip to main content. Editors: Benjamin Bonavida 0. Benjamin Bonavida Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, USA View editor publications.

Explores the most recent advances in the field of Nitric Oxide NO and its relationship to cancer Includes latest information on NO role in pathogenesis, gene and protein modifications, and therapeutic applications Contributions written by notable experts in the field Includes supplementary material: sn.

Sections Table of contents About this book Keywords Reviews Editors and Affiliations About the editor Bibliographic Information Publish with us. Buy it now Buying options eBook EUR Price includes VAT Germany.

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Page 1 Navigate to page number of 2. Front Matter Pages i-xxiii. Molecular Cell Signaling by NO in Cancer Front Matter Pages Geller Pages Nitric Oxide and Genomic Stability Vasily A.

Yakovlev Pages Targeting Hyponitroxia in Cancer Therapy Bryan Oronsky, Neil Oronsky, Michelle Lybeck, Gary Fanger, Jan Scicinski Pages Mechanisms of Nitric Oxide-Dependent Regulation of Tumor Invasion and Metastasis Aideen E. Ryan, Amy J. Burke, Francis J. Giles, Francis J. Sullivan, Sharon A.

Glynn Pages Role of Nitric Oxide in the Regulation of the Pro-tumourigenic Hypoxic Phenotype: From Instigation to Mitigation Lynne-Marie Postovit Pages S-Nitrosylation and Cancer Front Matter Pages Impacts of S-Nitrosylation in Cancer Tysha N.

Medeiros, Dana M. Jarigese, Melissa A.

Burke, Francis J. Giles, Francis J. Sullivan, Sharon A. Glynn Pages Role of Nitric Oxide in the Regulation of the Pro-tumourigenic Hypoxic Phenotype: From Instigation to Mitigation Lynne-Marie Postovit Pages S-Nitrosylation and Cancer Front Matter Pages Impacts of S-Nitrosylation in Cancer Tysha N.

Medeiros, Dana M. Jarigese, Melissa A. Edwards, Mark A. Brown Pages S-Nitrosylation in Cancer Cells: To Prevent or to Cause?

Ali Bettaieb, Stéphanie Plenchette, Catherine Paul, Véronique Laurens, Sabrina Romagny, Jean-Fran ois Jeannin Pages The Emerging Role of Protein S-Nitrosylation in Cancer Metastasis Sudjit Luanpitpong, Yon Rojanasakul Pages Modulation of Anti-tumor Immune Responses by NO Front Matter Pages Nitric Oxide, Immunity and Cancer: From Pathogenesis to Therapy Hermes J.

Garbán Pages Regulation of Anti-Tumor Immune Responses Peter Siesjö Pages Nitric Oxide: Immune Modulation of Tumor Growth Naveena B. Janakiram, Chinthalapally V. Rao Pages Therapeutics and Overcoming Resistance Front Matter Pages Pivotal Role of Nitric Oxide in Chemo and Immuno Sensitization of Resistant Tumor Cells to Apoptosis Benjamin Bonavida Pages Emerging Role of NO-Mediated Therapeutics Cian M.

McCrudden, Helen O. McCarthy Pages Photodynamic Therapy and Nitric Oxide Emilia Della Pietra, Valentina Rapozzi Pages Regulation of Cell Death Signaling by Nitric Oxide in Cancer Cells Jordi Muntané, Francisco Gallardo-Chamizo, Sheila Pereira, Ángela M.

De los Santos, Ángeles Rodríguez-Hernández, Luís M. Marín et al. Pages Back to top. About this book Advances in Nitric Oxide and Cancer is a volume that serves to give the latest research on nitric oxide NO and cancer. More specifically, the volume reviews significant advances in the application of NO-mediated drugs.

The volume explores nitric oxide and its relationship to cancer spanning from its roles in the pathogenesis, prognosis, gene and protein modifications, regulation of resistance to cytotoxics, and therapeutic applications.

With chapters written by leading experts, the volume addresses the burgeoning interest in a rapidly advancing field and provides a valuable resource to scientists who have initiated research as well as clinical investigations in their laboratories on the various roles of NO and cancer.

Keywords Nitric oxide therapy S-nitrosylation cytotoxics nitrosylation pleiotropic regulator antibacterial drug resistance. Editors and Affiliations Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, USA Benjamin Bonavida Back to top.

About the editor Dr. His other appointments include being a member of the Department of Defense Congressionally Directed Medical Research Program, Member of the National Cancer Institute's SPORE Program, member of the International Scientific Advisory Board of the Israel Cancer Research Foundation, to name a few.

Publish with us Policies and ethics. Access via your institution. search Search by keyword or author Search. Navigation Find a journal Publish with us Track your research. Yang and colleagues found that tissue expression of iNOS and p53 is significantly correlated with tumor stage and pathologic grade of oral SCC, but there is no correlation with lymph node metastasis.

The OSCC survival rate was negatively associated with survival rate GSCs can be distinguished from non-GSC and normal neural progenitors because GSCs depend on NOS2 activity for growth and tumorigenicity Elevated iNOS expression correlates with decreased overall survival in human glioma patients Table 2 further describes a range of preclinical studies in various solid tumors showing that iNOS-directed therapies may be effective at targeting chemoresistant CSC populations and metastasis.

L-NMMA combined with docetaxel enhanced apoptosis of TNBC cells. Combining docetaxel and L-NMMA significantly decreased tumor volume and improved overall survival. Selective iNOS W and pan-NOS L-NMMA inhibitors decreased cell proliferation, migration, CSC self-renewal capacity, and reversed EMT.

iNOS inhibition reduced the number of lung metastases and tumor initiation and augmented the efficacy of taxane chemotherapy. RPL39 oncogenic function was mediated through inducible NOS; high expression of RPL39 and iNOS is associated with poor overall survival in MpBC patients.

Radiotherapy RT enhanced the expression of iNOS from PDAC tumors and activated cancer-associated fibroblasts to express iNOS, release NO, and produce inflammatory cytokines via activation of NF-κB. L-nil treatment suppressed the growth of melanoma tumors and extended overall survival in an immunodeficient mouse xenograft model.

L-nil inhibited the formation of intratumoral nitrotyrosine, decreased tumor microvessel density, downregulated Bcl-2 expression, and induced intratumoral apoptosis in vivo. iNOS mRNA and protein expression were increased in human ICC tumors and positively associated with complicated bile duct stone formation, expression of matrix metalloproteases MMPs , poor tissue differentiation, and expression of Wip1.

iNOS knockdown and pharmacologic inhibition suppressed cell proliferation, invasion, and migration; induced G 0 —G 1 cell-cycle arrest and apoptosis; and reduced expression of Wip1, MMP2, and MMP9. iNOS inhibition impairs LCSC tumor initiation and self-renewal capacity in vitro and in vivo.

Combination treatment of chemoradiotherapy CRT , L-nil, and cyclophosphamide CTX remodeled the tumor myeloid microenvironment, including the recruitment of antitumor immune cells and decrease in immunosuppressive granulocytic MDSCs.

iNOS derived from melanoma tumors may recruit and induce functional MDSCs by modulating VEGF secretion and upregulating the expression of STAT3 and ROS. DA suppressed tumor growth of SAS oral cancer xenograft tumors relative to vehicle control treatment.

DA treatment in oral cancer cells leads to enhanced expression of LC3-II, reduced p53 expression, activated JNK signaling, and inhibition of Akt and p38 signaling. A multicomponent nanoparticle called Fe MSN, containing a mesoporous silica shell and iron oxide core, was developed and loaded with W.

Fibronectin-targeting ligands directed the nanoparticles to perivascular areas of GBM, and external radiofrequency triggers drug release across the blood—brain barrier. EMT is a cellular process in which an epithelial cell with apical—basal polarity undergoes multiple biochemical changes to transition into a quasi-mesenchymal cell state 73, These mesenchymal-like cells have enhanced invasiveness, migratory capacity, resistance to apoptosis, stem-like features and produce extracellular matrix components NO's influence on pro-and antimigratory properties of tumor cells mediated by EMT depends on NO concentration A high flux of NO prevents NF-κB activity by either S-nitrosation of the p50 subunit of NF-κB, reducing DNA-binding activity, or by inhibition of phosphorylation and dissociation of IκBα.

Snail, a key EMT transcription factor, is transcriptionally induced by NF-κB but inhibited by E-cadherin and metastasis-suppressor Raf-1 kinase inhibitor protein RKIP; ref. In human metastatic prostate cancer cell lines treated with supraphysiological concentrations of NO via NO donor DETA NONOate, there was a reduction in Snail expression, upregulation of E-cadherin and RKIP, and a reversal of mesenchymal phenotype and cell invasive properties In an alveolar epithelial cell model that recapitulates features of human interstitial lung disease idiopathic pulmonary fibrosis and bronchopulmonary dysplasia , exogenous NO reduces EMT reduced collagen I and alpha-smooth muscle actin expression.

In contrast, treatment with L-NAME pan-NOS inhibitor causes a spontaneous increase in EMT The promigratory properties associated with NO signaling have also been reported in other studies.

NO regulates EMT programming via modulating the expression of TGFβ, a critical inducer of EMT 79, Another study supported these findings by showing that selective pharmacologic and siRNA-based inhibition of iNOS in TNBC breast cancer cell lines MDA-MB and SUM leads to decreased cellular migration and reduced protein expression of EMT transcription factors Snail, Slug, Twist1, and Zeb1; ref.

Other than targeting TGFβ and ER stress pathways, NO can also induce EMT via the induction of EGFR-dependent ERK phosphorylation This finding indicates that chronic NO exposure can lead to the acquisition of a protumorigenic phenotype in the prostate. These findings were further recapitulated in prostate cancer cells PC3 and DU, thereby increasing further their invasive potential The expression of iNOS was predominantly elevated in human ICC tissues compared with adjacent normal biliary tissue and was strongly associated with metastasis and poor differentiation.

In ICC cell lines QBC and ICC, iNOS inhibition with W small-molecule inhibitor resulted in decreased cellular invasion and migration, suggesting that iNOS partly facilitates ICC metastatic capacity.

siRNA knockdown of NOS2 in ICC cell lines leads to decreased mRNA expression of MMP9, MMP2 , and PPMI1D , genes involved in tumorigenicity and metastasis.

Overall, these studies emphasize the nuanced and concentration-dependent complexity of the influence of NO on EMT and migratory capacity.

A preventable risk factor associated with EMT, migratory capacity, and maintenance of CSC populations is obesity. In a study using murine models of claudin-low and basal-like breast cancer, dietary energy balance [calorie-restriction or diet-induced obesity DIO ] differentially modulated EMT and tumor progression DIO promoted tumor progression and EMT, as evidenced by enhanced expression of N-cadherin, fibronectin, and decreased expression of E-cadherin in mammary tumors.

In both claudin-low and basal-like tumor models, DIO promoted the expression of EMT and tumor-initiating cell TIC genes, such as TGFβ, Snail, FOXC2 , and Oct4 , which are modulated by obesity-related growth factors 88— In murine syngeneic models of TNBC, high-fat-diet treatment is associated with enhanced tumoral hypoxia, neutrophil infiltration, decreased vascularity, EMT programming, and retention of tumor-initiating CSCs relative to mice treated with regular diet These findings suggest that obesity-associated factors that have yet to be identified may be critically involved in promoting an aggressive TNBC phenotype in patients with obesity.

Furthermore, fatty tissue inflammation associated with obesity results in the production of critical inflammatory modulators, such as COX2, prostaglandins PG , and NO These eicosanoids and inflammatory modulators are crucial for the development and growth of breast cancers, either via the production of aromatase for estrogen-dependent breast cancers or directly promoting an aggressive phenotype in estrogen-independent breast cancers [via NO and Prostaglandin E2 PGE2 production; refs.

Despite many studies implicating obesity as a preventable risk factor associated with enhanced metastatic capacity and EMT, the obesity-associated factors responsible for this tumor phenotype are relatively unknown. Recently, NO has been implicated as a molecule that may explain the connection between obesity, diet, and metastasis.

The link between obesity and cancer, particularly its influence on metastasis, has not been delineated. According to the International Agency for Research on Cancer IARC , excess body fat was linked to 13 cancers, such as postmenopausal breast cancer The current approach of utilizing BMI as a surrogate marker in relation to cancer risk may not completely capture the complexities associated with adipose TME and tumorigenesis Instead, a better marker would be evaluating the quality of adipose tissue, particularly in response to body-weight gain or metabolic obesity DAMPs such as free fatty acids, lipid metabolites, thioredoxin-interacting protein, s proteins, nucleic acids, cholesterol, and ATP trigger an innate immune response composed of dendritic cells, macrophages, and granulocytes , the formation of crown-like structures, and proinflammatory responses 98, This obesity-associated chronic proinflammatory response enhances vascular inflammation and permeability, leading to cancer cell dissemination.

In mouse models, obesity can lead to increased lung neutrophilia associated with experimental and spontaneous breast cancer metastasis to the lung in a neutrophil-dependent manner This is likely due to an impairment in vascular integrity through loss of endothelial adhesions through obesity-induced lung neutrophils, resulting in cancer cell extravasation to the lung McDowell and colleagues found that relative to neutrophils from lean mice, neutrophils from obese mice expressed genes related to reactive oxygen species ROS , such as NOS2 , and had low expression of genes essential for antioxidant activity as CAT.

Specifically, neutrophil-produced reactive oxygen and nitrogen species, such as NO, increased the formation of neutrophil extracellular traps NETosis , which weakened vascular integrity. These findings suggest that obesity is associated with oxidative stress markers, such as NOS2 and NETosis, during lung metastases.

Therefore, targeting these pathways with lifestyle modifications and NOS inhibitors may decrease metastatic risk in patients with obesity. There are a few preclinical studies that evaluated the benefit of combining NOS-targeted therapies with radiotherapy that are relevant to our discussion.

Pharmacologic inhibition of NOS with the small-molecule inhibitor W augmented therapeutic response to radiotherapy and decreased PDAC orthotopic tumor growth Comparable findings were found in a preclinical study using a murine human head and neck squamous cell carcinoma HNSCC model These findings in PDAC and HNSCC models suggest that inhibiting the immunosuppressive enzyme iNOS may be critical to remodel the tumor microenvironment and augment the efficacy of chemoradiotherapy.

The findings from promising preclinical studies have spurred interest in the clinical translational of NOS-targeted therapies for various cancers Tables 1 and 2.

There are no NOS-based targeted therapies approved by the FDA. However, a few ongoing clinical trials have evaluated whether NOS inhibition via L-NMMA can boost the efficacy of taxane-based chemotherapies and immunotherapies and assess its influence on the TME Table 3.

L-NMMA combined with taxane-based chemotherapy was tested in patients with chemorefractory, locally advanced breast cancer LABC and metastatic TNBC The study found an overall response rate of Remodeling of the tumor immune microenvironment was found in patients who responded to the combined therapy.

These findings shed light on the importance of exploring the role of iNOS inhibition in remodeling the TME and augmenting the efficacy of systemic therapies in multiple cancer types. Overall response rate was Nonresponders showed elevated expression of markers associated with M2 polarization and increased expression of IL6 and IL10 cytokines.

Despite many promising preclinical studies, there have been challenges contributing to the scarcity of clinical trials with NOS inhibitors. One example is that the biphasic role of NO complicates the regimen of choice for NO-based therapies, making this therapeutic strategy difficult in clinical settings.

Another challenge is developing a standardized approach to decide what patients would benefit the most if NOS inhibitors were incorporated into their treatment arsenal and how would this decision be made.

This may be mediated by NO inactivating p53 function, either via loss of DNA-binding activity or selecting for mutant TP53 — Therefore, along with iNOS IHC staining, evaluating TP53 mutation status may also be worthwhile as a combined biomarker to determine whether a patient should receive a NOS inhibitor.

Another limitation that may explain why there is a scarcity of oncology clinical trials evaluating the efficacy of NOS inhibitors is that certain animal models may not be highly predictive of outcomes in human clinical trials Differences in the inducibility and relevance of NOS2 in rodents and humans may also contribute to why preclinical studies do not completely recapitulate clinical trial outcomes 65, Another concern is the potential off-target effects associated with NOS inhibitors, particularly pan-NOS inhibitors such as L-NMMA.

These can include hypertension and decreased cardiac output due to their inadvertent inhibition of the eNOS isoform. Cautionary tales from the negative results of the phase III TRIUMPH trial, in which L-NMMA was tested in patients with cardiogenic shock postmyocardial infarction, may have steered clinical trialists from using NOS inhibitors in other clinical settings However, the early cessation of the TRIUMPH trial was because L-NMMA did not reduce overall mortality; however, L-NMMA was well tolerated with a safe toxicity profile Although there are doubts about using nonselective NOS inhibitors for cardiogenic shock, repurposing its use in anticancer therapies should be considered.

L-NMMA-induced hypertension can be well managed with antihypertensive medications, such as amlodipine. Further progress on appropriately utilizing NOS inhibitors in the clinical setting of oncology is still needed and should be seriously considered.

There is still a crucial need to develop and test therapies that can impair metastatic processes and target chemoresistant, tumor-initiating CSCs. Here, we reviewed the roles of NO as a critical molecule in regulating metastasis via PTMs, altering EMT programming, maintaining CSC populations, and driving obesity-associated metastasis.

Although a few emerging clinical trials evaluate NOS inhibitors as anticancer interventions, a more detailed understanding of NOS's biphasic role in tumor progression and standardized approaches to decide which patients with cancer would benefit the most from this therapeutic is necessary.

Glynn reports grants from Science Foundation Ireland during the conduct of the study. Billiar reports a patent for human NOS2 cDNA and recombinant protein issued. Chang reports a patent for methods for treating cancer using iNOS-inhibitory compositions issued.

No disclosures were reported by the other authors. This project was funded in whole or in part by the Breast Cancer Research Foundation BCRF ; philanthropic support from M. Neal and R. Neal; National Cancer Institute, NIH, grant no. U01 CA to J. Chang ; and under Contract HHSNE to D.

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Skip Nav Destination Close navigation menu Article navigation. Volume 29, Issue Previous Article Next Article. Overview of NOS Signaling. S-Nitrosation and Cancer Metastasis.

The Influence of NO on Cancer Stem Cells. The Influence of NO on EMT. Obesity-Associated iNOS and Metastasis. NOS Targeted Therapy Combined with Radiotherapy. Prospects and Challenges for Clinical Translation of NOS-Targeted Therapy in Oncology.

Authors' Disclosures. Article Navigation. Reviews May 15 Targeting Nitric Oxide: Say NO to Metastasis Tejaswini P. Reddy This Site. Google Scholar. Sharon A. Glynn Timothy R. Billiar David A. Wink Jenny C. Chang Chang, Cancer Center, Houston Methodist Research Institute, Main Street, Floor 24, Houston, TX Phone: ; Fax: ; E-mail: jcchang houstonmethodist.

Clin Cancer Res ;— Received: September 08 Revision Received: October 24 Accepted: December 02 Online ISSN: Funding Group: Award Group: Funder s : National Cancer Institute NCI. This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.

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Figure 1. View large Download slide. Figure 2. Table 1. Biological role of NOS in cancer progression and metastasis. Cancer type. Biological role. Triple-negative breast cancer TNBC - The novel cancer gene ribosomal protein L39 RPL39 is responsible for stem cell self-renewal, treatment resistance, and lung metastases in TNBC.

Pancreatic adenocarcinoma PDAC - Pancreatic tumors typically harbor elevated expression of iNOS relative to normal pancreatic tissue Head and neck squamous cell carcinoma - In HNSCC, MDSCs are known drivers of immunosuppression, and their enzymes arginase-1 and iNOS are critical drivers of immunosuppression by inactivating effector T cells Intrahepatic cholangiocarcinoma - The expression of iNOS is predominantly elevated in human ICC tissues compared with adjacent normal biliary tissue and is strongly associated with metastasis and poor differentiation Gastric cancer - iNOS can induce the expression of VEGF in gastric cancers, and expression of both genes leads to enhanced angiogenesis Oral squamous cell carcinoma SCC - iNOS mRNA expression and NO production are increased in human oral SCC tissues relative to normal oral epithelium and dysplastic tissue Glioblastoma - GSCs can be distinguished from non-GSC and normal neural progenitors because GSCs depend on NOS2 activity for growth and tumorigenicity View Large.

Table 2. Preclinical studies utilizing iNOS inhibitors as anticancer therapeutic. Models used in the study. L-NMMA Pan-NOS TNBC TNBC cell lines SUMPT, MDAMB, MDAMB and PDX models BCM, BCM, BCM, BCM, HM - L-NMMA combined with docetaxel enhanced apoptosis of TNBC cells.

Table 3. NOS inhibition as a cancer therapeutic in clinical trials. NCT number. NCT Search ADS. Tumor microenvironment complexity and therapeutic implications at a glance. Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K murine melanoma cells.

Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K murine melanoma cells. Activation of nitric oxide synthase gene for inhibition of cancer metastasis.

Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine. Nitric oxide, prostanoids, cyclooxygenase, and angiogenesis in colon and breast cancer.

Heme proteins and nitric oxide NO : the neglected, eloquent chemistry in NO redox signaling and regulation. The ferrous-dioxy complex of neuronal nitric oxide synthase: divergent effects of L-arginine and tetrahydrobiopterin on its stability.

Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression.

Redox signaling: nitrosylation and related target interactions of nitric oxide. nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. S-nitrosothiols and the bioregulatory actions of nitrogen oxides through reactions with thiol groups.

Mechanisms of inducible nitric oxide synthase-mediated vascular dysfunction. Nitric oxide modulates metabolic processes in the tumor immune microenvironment. The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species: putting perspective on stressful biological situations.

Molecular mechanisms of nitric oxide in cancer progression, signal transduction, and metabolism. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes.

Thioredoxin and cancer: a role for thioredoxin in all states of tumor oxygenation. S-nitrosylated and non-nitrosylated COX2 have differential expression and distinct subcellular localization in normal and breast cancer tissue.

Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. S-nitrosylation at cysteine of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion.

S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer. Regulation of ezrin tension by S-nitrosylation mediates non-small cell lung cancer invasion and metastasis. Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation.

Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. iNOS associates with poor survival in melanoma: a role for nitric oxide in the PI3K-AKT pathway stimulation and PTEN S-nitrosylation.

NO can also inhibit apoptosis via cell death protective protein expression, radical—radical interferences and S -nitrosylation of caspases at their active site cysteines and cGMP Inhibition of apoptosis by NO has been observed in endothelial cells, lymphoma cells, ovarian follicles, cardiac myocytes, vascular smooth cells and hepatocytes Both exogenous NO donor and NOS transfection and endogenous proinflammatory mediators NO inhibited transforming growth factor-β1-induced EMT and apoptosis in mouse hepatocytes In primary B-cell cultures isolated from B-cell chronic lymphocytic leukemia patients, the introduction of l -NAME substantially increased apoptotic DNA fragmentation in B-cell chronic lymphocytic leukemia cells Endothelial cells pretreated with proinflammatory cytokines or NO donor mediated an increase in Bcl-2 expression and inhibition of Bax protein and consequently protected cells from ultraviolet A-induced apoptosis.

This effect was abrogated by addition of NOS2 inhibitor Tumor necrosis factor-α and actinomycin-D-treated MCF-7 cells treated with NO donors showed an inhibition of Bcl-2 cleavage and cytochrome c release, leading to blockage of apoptosis and caspaselike activation Apoptosis is induced and preneoplastic colonic lesions are prevented through the inhibition of NOS2 and NF-κB when dolastatin, a mollusk linear peptide, and celecoxib, a selective cyclooxygenase-2 inhibitor are used Glycochenodeoxycholate-induced apoptosis of hepatocytes can be enhanced or abrogated by NO.

The use of NO donors again demonstrated NOs dual role in apoptosis: low concentrations 0. Therefore, in this case, endogenous iNOS inhibited apoptosis, but the exogenous NO played a dual role during the glycochenodeoxycholate-induced apoptosis The effects of NO on radiation are not clearly understood.

However, reports suggest that NO confers both radiosensitization and radioprotection to tumor cells In human lung cancer, H cells expressing wtp53, a range of NO concentrations induced opposing effects on radiosensitivity and chromosome aberrations, depending on cell cycle phase , Using NO donors and NOS inhibitors, NO extended significant radioprotection to mice receiving whole body irradiation Radioprotection of soft tissue and prevention of apoptosis in irradiated mouse muscle in vivo were observed presumably by increasing NO levels through inhibition of CD expression The radiosensitivity of A and H non-small cell lung cancer cells was enhanced by reduction in the levels of NO induced by radiation and N G -monomethyl- l -arginine-monoacetate Tumor growth was enhanced by irradiation-induced increased NOS3, accompanied by endothelial cell migration, sprouting and formation of capillary-like structures on matrigel plugs implanted in mice, thereby demonstrating an increase in angiogenesis.

Irradiation dose dependently induced the activation of the proangiogenic NO pathway in endothelial cells via NOS3 expression and phosphorylation Use of NOS inhibitor l -NNA repressed irradiation-induced NO-mediated angiogenesis.

NO can radiosensitize mammalian cells and especially hypoxic cells Oxygen concentration is critical. This illustrates that NO can confer radiosensitivity to tumor cells. Stewart et al.

This is promising for adjuvant therapy to radiation for prostate cancer patients. In colorectal cancers, NO and ionizing radiation work together to activate p53, inducing apoptosis and increasing radiosensitivity Also radiosensitization of tumor cells by NOS2 endogenous production of NO via, proinflammatory cytokines was transcriptionally controlled by hypoxia and NF-κB The involvement of NO in the field of epigenetics has recently emerged.

Epigenetics is defined as heritable changes to chromatin, which regulate gene expression without altering the underlying DNA sequence Epigenetic mechanisms include DNA methylation, small RNA activity and histone modifications, each of which can be modulated by NO One mechanism of epigenetic contribution to oncogenesis is via DNA hypermethylation, leading to gene silencing and downregulation of tumor suppressor gene expression NO regulates epigenetic effects both directly and indirectly.

NO can be synthesized in the nucleus, thereby enabling its direct effects, by impacting functional activity of histone-modifying enzymes, e. histone deacetylase 2 in neurons 5. NO-dependent histone modification includes hyperacetylation of histone H3 in oral cancer, correlating with upregulated nucleophosmin and glyceraldehydesphosphate dehydrogenase levels Epigenetic regulation is important in cellular reprogramming.

This led to reduced proliferation and chromatin relaxation, and increased the expression of miRa, miR and miRa. Whether NO has similar effects on cancer stem cells is unknown. Indirect epigenetics includes S -nitrosylation and regulation of transcription factors e.

NF-κB, HIF-1 and activating protein 1 Also tyrosine-nitration can mediate NO epigenetic effects. Yakovlev et al. In contrast, tyrosine-nitration of p53 in human glioblastoma led to protein inactivation Introduction of eNOS inhibitor reversed GSTP1 gene silencing Colorectal cancer carcinogenesis may be influenced by NO-mediated epigenetic regulation.

Colonic inflammation induction in a rat model using 2,4,6-trinitrobenzene sulfonic led to intercellular adhesion molecule-1 expression by translocation of NF-κB to the nucleus. Using the NO donor GSNO, NF-κB DNA binding could be blocked, via transcriptional downregulation of global histone deacetylase 3 and decreased DNA interaction at the intercellular adhesion molecule-1 promoter containing the binding motifs of NF-κB, and suppression of H4K12 acetylation, thus suppressing inflammation Deletion of NOS2 in a murine lung cancer model decreased tumor growth, mir expression and inflammatory responses initiated by oncogenic KRAS, suggesting cooperation between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and NOS2 in lung tumorigenesis and inflammation It comes as no surprise that NO has been exploited as an anticancer target for some time.

Various approaches have been investigated, including NO as radiotherapy and chemotherapy sensitizers, NOS inhibitors and novel NO-donating drugs 5.

In a phase II study, low doses of NO releasing glyceryl trinitrate were administered to prostate cancer patients following primary treatment failure. NO significantly reduced hypoxia-induced cancer progression, as measured by prostate-specific antigen doubling time SNAP and GSNO , which are effective antiproliferative agents against many cancer cell lines 5.

Investigation of the inhibitory effect of JS-K on androgen receptor signaling in castration resistant 22Rv1 prostate cancer cells, showed attenuation of intracellular functional androgen receptor, due to generation of high NO levels, coupled with significant growth inhibition NO-NSAID donor drugs are potential anticancer drugs derived from traditional NSAIDs, modified to include NO-releasing moiety via a linking spacer NO-NSAIDs were originally developed to overcome side effects of NSAIDs, such as gastrointestinal complications, while maintaining the positive effects of the parental NSAID in addition to the anticancer properties of NO NO-NSAIDs exert their anticancer function through inhibition of proliferation and cell cycle, induction of apoptosis and modulation of Wnt and NF-κB signaling pathways NO-NSAIDs inhibited HT colon adenocarcinoma cells substantially more so than the parental NSAID alone It remains unclear, however, whether it is in fact the NO moiety that infers its biological effects, as opposed to the spacer NOS inhibitors have also been studied extensively.

Significant reduction in lung metastasis, correlating with a reduction in microvessel density and an increase in tumor stroma and parenchyma, was also noted The weakly tumorigenic and non-metastatic fibrosarcoma QR assume a highly malignant tumor phenotype once transplanted in vivo along with gelatin sponge into C57BL6 mice.

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.

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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.

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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.

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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. Controversial associations have been found with smoking or drinking habits [ 61 ]. The three enzymatic sources of NO, nNOS, eNOS, and iNOS, have been characterized in the gastrointestinal tract [ 62 ].

There is enhanced expression of iNOS and eNOS in human colorectal cancers [ 63 ]. Colon cancer tissue has also been found to express NOS mRNA [ 64 ]. Gastric carcinogenesis GC is considered as a multistage progressive process. The early indicator for GC predisposition is abnormal hyperproliferation of gastric epithelial cells, such as chronic atrophic gastritis CAG , dysplasia DYS and intestinal metaplasia IM , which have been considered as precancerous lesions of GC [ 65 , 66 ].

In a study by Feng et al. The study demonstrated that the positive immunostaining rates of iNOS were correlated well with GC lymph node metastasis. All these findings suggested a role of NO in the initiation and progression of GC.

NOS can also deaminate DNA and cause mutations of tumor suppressor genes, and possibly other oncogenes, such as c-met, and initiate genetic alterations of gastric cells leading to gastric malignancy [ 23 ]. GC may be considered the result of interplay between host genetic profile and environmental toxic agents [ 67 ].

The link between H. pylori infection and GC has been demonstrated by epidemiological data and in experimental animal models [ 68 — 71 ]. Overproduction of NO via inducible iNOS is suggested to be a significant pathogenic factor in H. pylori -induced gastritis [ 72 ]. Exposure of gastric epithelial cells to bacterium results in the generation of reactive oxygen species ROS and iNOS that, in turn, may cause genetic alterations leading to GC in a subset of subjects [ 67 ].

An increasing frequency of p53 abnormalities occurs as the gastric mucosa progresses from gastritis, through IM, DYS, and early to advanced invasive GC [ 73 ]. C to T mutations in p53 are induced by NO [ 74 , 75 ] which might have been produced during H.

pylori infections. Based on these facts, it can be said that H. pylori may lead to GC through overproduction of NO, as one of the mechanisms. NO influences a great variety of vital functions including vascular tone and neurotransmission.

NO emerges as an important mediator of neurotoxicity in a variety of disorders of the central nervous system CNS. nNOS expression may act as a putative useful indicator of brain tumor differentiation and malignancy [ 75 ].

Cobbs et al. examined human brain tumors for three NOS isoforms and NADPH diaphorase, a histochemical marker of NOS activity in the brain. Data of their study suggested that malignant central nervous system neoplasms express unexpectedly high levels of NOS and suggest that NO production may be associated with pathophysiological processes important to these tumors [ 76 ].

Oral squamous cell carcinoma OSCC is the sixth most common malignancy and a major cause of morbidity and mortality [ 77 ]. The high incidence of oral cancer and oral pre-cancer has been linked with habits of tobacco chewing and smoking [ 78 , 79 ].

Raised levels of NO 2 and NO 3 were noted in patients with oral pre-cancer [ 81 , 82 ] and in healthy individuals with tobacco habit [ 80 , 81 ]. This indicates potential of nitrosative injury in tobacco users and,therefore, NO may have clinical relevance as a biomarker of inflammation and estimation of cancer risk in pre-cancer patients or in healthy tobacco users.

Alcohol intake is related to an increased predisposition to oral cancer [ 83 ]. Cooper and Magwere suggested that stimulation of NO production by ethanol is likely to play an important role in the etiology of some cancers, including head and neck cancer, which preferentially rely on NO signaling [ 84 ].

Taken together, these facts implicate the role of NO in development of oral cancer. Very few studies have evaluated the role of NO in oral pre-cancer.

Whether NO actually acts as a protumoral agent at a concentration which is present in oral pre-cancer needs further evaluation. Studies are required to know the exact role of NO in oral pre-cancer which will be helpful in intervening the cancer process.

The steady increase in the incidence of oropharyngeal cancers over the last four decades has been mainly attributed to oral HPV infection, which has been accepted as an etiological factor for a subset of head and neck squamous cell carcinoma HNSCC [ 85 — 88 ].

HPV-positive HNSCCs have a unique risk factor profile. These tumors are more common in younger patients, have a male predominance, and are often staged higher, yet have a survival advantage. These patients are less likely to have used tobacco and alcohol excessively [ 89 ].

An association between chronic inflammation such as through HPV infection and oral cancer is biologically plausible. It is known that chronic inflammation can lead to the production of NO which in turn can mediate DNA damage. Considering these facts, the role of NO in HPV associated head and neck cancer in patients without habits, needs an evaluation.

Although several reports have addressed the protumoraleffects of NO, as mentioned above, few have demonstrated the contrasting role of NO in mediating tumor regression [ 9 , 90 , 91 ].

It has been reported that NO derived from macrophages, Kupffer cells, natural killer cells, and endothelial cells participates in tumoricidal activity against many types of tumors [ 90 , 92 ].

NO has been proposed to cause suppression of DNA synthesis through the salvage pathway [ 93 ]. Long standing overproduction of NO acts as a proapoptotic modulator, activating caspase family proteases through the release of mitochondrial cytochrome C into the cytosol, upregulation of p53 expression, and alterations in the expression of apoptosis-associated proteins including the Bcl-2 family [ 24 ].

A high NO level has been proposed to suppress metastasis [ 94 ]. Baritakiet al. have shown that high levels of NO derived from the NO donor DETA-NONOate inhibits epithelial-mesenchymal transition EMT and reverses both the mesenchymal phenotype and the invasive properties of human prostate metastatic cells [ 95 ].

Findings of the study by Bonavida et al. have also suggested that NO donors may prove to be potential therapeutic agents in both reversal of drug resistance and the inhibition of EMT and metastasis [ 96 ]. Although these tumoricidal roles of NO have been proposed, most experiments have been performed in vitro [ 11 , 97 ] and such findings have not been reported in cancer patients.

It has been suggested that NO concentrations found in OSCC and other solid tumors are insufficient to produce apoptosis [ 98 ] and other tumoricidal effect and are likely to facilitate angiogenesis and tumor dissemination [ 99 ].

Further, whether NO has an inhibitory or stimulatory effect on the cancer process initially depends on the concentration of NO achieved and also on other factors such as the type of cell exposed, the redox state, final intracellular concentration, duration of exposure, etc.

Once the cancer has begun, NO seems to play a protumoral role rather than antitumoralone as the concentration required to cause tumor cell cytotoxicity cannot be achieved by cancer cells [ ].

These characteristics of NO have been exploited therapeutically with impressive effects in pre-clinical models of cancer to slow tumor growth and to enhance the efficacy of both chemotherapy and radiotherapy [ ].

Researchers are investigating various strategies for manipulating in vivo production and exogenous delivery of this molecule, includingiNOS gene therapy, iNOS induction, and administration of NO donor drugs [ 94 ] for therapeutic gain.

Transfer of NOS-encoding cDNA sequences into cancer cells for gene therapy purposes was thought to be one of the mechanisms for delivery of NO.

However, as both retroviral and adenoviral vectors may be hazardous to the host, cell-based approaches to overcome the problems associated with gene therapy [ ] are being sought. Further work into the precise mechanisms of this process is required.

Alternative mechanisms for NO delivery would be the use of NO releasing drugs or NO donors. These are capable of causing sustained release of NO with a wide range of half-lives, and with predictable estimated doses. They can simultaneously exert a multitude of anticancer activities including enhancement of apoptotic stimuli, inhibition of metastasis, inhibition of angiogenesis, and inhibition of hypoxia, depending on concentration of NO donor and on the cancer type and stage [ ].

Several promising findings strongly support the therapeutic application of NO donors in cancer treatment, used alone or in combination with other subtoxic doses of cytotoxic agents. NO donors have been shown to have the dual function of both sensitizing tumor cells to chemotherapy and immunotherapy and of being involved in the regulation and inhibition of metastasis [ ].

NO donors belonging to the class of diazeniumdiolates are promising as they have been shown to be effective chemo- and radio-sensitizing agents along with other attractive properties such as long half-lives and target tissue specific delivery.

The role of nitro-glycerine as a chemo-sensitizing agent as demonstrated by Yasuda et al. According to Bonavida and Baritaki [ ], NO donors may be considered as novel potential therapeutic agents with dual roles in the treatment of patients with refractory cancer and in the prevention of the initiation of the metastatic cascade via EMT.

However, the therapeutic application of NO donors has been limited by potential systemic effects exerted in vivo. These adverse effects include vasodilation leading to pronounced hypotension and accumulation of toxic metabolites such as cyanide [ ]. The need to develop the ideal NO donor with maximal anti-proliferative properties and minimal side effects has led to the invention of NO-hybrids.

NO-hybrids are providing a unique niche in the armamentarium of anticancer agents. Combining NO to existing drugs affords an advantage of adding or potentiating the effects of NO to the benefits of drugs like NSAIDs or statins.

NO-drug hybrids such as NO-NSAIDs demonstrate promise as anti-cancer agents and are in clinical trials by NCI-sponsored phase I randomized studies i. The synthesis of molecules capable of releasing optimal amounts of NO at the right time and the right place poses a great challenge to pharmaceutical research.

NO donors can be incorporated into or chemically linked to biopolymers, mimicking endogenous NO production at a target site [ , ]. Nanomaterials are currently being harnessed to load high amounts of NO; they are quite stable, are sometimes photoactive, and possess demonstrable biological activity.

Their surfaces can also be chemically modified and optimized for specific medical applications. They may facilitate the development of systems for simultaneous therapeutic and diagnostic applications [ ].

These nanoparticles can be prepared by physiochemical, chemical, and mechanical methods [ ]. However, drug release from particles may vary according to the polymer used or the drug encapsulated [ ].

Nanocarriers of NO make the agent more available to systemic circulation and can also enhance the NO target [ ]. A small number of reports have been published on the topical delivery of NO using polymeric systems. Kanayama et al. Friedman et al. reported that therapeutic levels of NO, in controlled and sustained manner, can be achieved by using combination of glassy matrices and hydrogels [ ].

This system exhibited improved stability in the skin and NO release by visible light irradiation, with potential applications in the treatment of skin cancer [ ].

Stevens et al. engineered NO-releasing SiNPs for NO delivery to human ovarian cancer cells for their inhibition [ ].

Another class of liposomes that can be successfully used as nanocarriers are thermosensitive liposomes; they can be employed in the storage, delivery, and active release of NO in a heat-mediated manner [ ]. These thermo-sensitive liposomes containing NO may have applications in anticancer therapeutics as heat is generated in tumor tissue [ ].

Fluorescent nanocrystals, also known as quantum dots QDs can be linked to NO-donor molecules. These can specifically lead to effective treatment of large tumors by photodynamic therapy [ — ].

In this case, the nitrosyl compounds can generate, under light application, ROS and NOS via QD excitation, enabling tumor cell death [ — ]. The preliminary in vitro experiments with neuroblastoma cells have demonstrated that the combination of nano-delivery and chemotherapy enhances antitumor activity of chemotherapeutics [ ].

Current nanotechnology-based systems are highly promising but there are currently no commercially available nano- or microcarriers for NO delivery. Giles et al. have recently reported the development of two photolabileNO-releasing prodrugs, tert-butyl S-nitrosothiol and tert-dodecane S-nitrosothiol.

They confirmed that irradiation induced highly significant increase in cytotoxicity in A lung carcinoma cells by these drugs. These prodrugs can be further explored to have applications in chemical biology studies and chemotherapy [ ].

Thus NO appears to be a potentially promising agent for the treatment of cancer and prevention of metastatic cascade and therefore further studies are required to clearly understand the complex and wide-ranging roles of NO in order to facilitate its therapeutic use.

NO is a relatively stable, free radical gas that readily diffuses into cells and cell membranes where it reacts with molecular targets. The precise reactions of NO depend on the concentration of NO achieved and on subtle variations in the composition of the intra- and extracellular milieu.

NO seems to play a part in various stages of carcinogenesis from initiation to progression. Expression of NOS have been detected in various human cancers. In breast cancer both the development of primary tumor and the process of metastasis seems to be influenced by the presence and amount of NO.

In cervical carcinogenesis it acts as a molecular cofactor with HPV infection. Exhaled breath analysis and exhaled NO measurement may provide useful assays in providing diagnosis and disease progression in lung cancer. NO can initiate genetic alterations of gastric cells leading to gastric malignancy.

Exposure of gastric epithelial cells to H. pylori bacterium may result in the generation of ROS and iNOS which in turn may cause genetic alterations leading to GC. Various studies have suggested a role of NO in the development of head and neck cancer. Thus NO seems to have an important part in the initiation, growth, and metastasis of various cancers.

However, it is said to have a tumoricidal role as well. However, this depends on various factors and once the cancer begins, NO seems to play protumoralrather than an antitumoral role.

On the other hand, the tumoricidal properties of NO are being utilized in the treatment of cancer. NO can act as a novel potential therapeutic agent in patients with refractory cancer by sensitizing tumor cells to chemotherapy, radiotherapy or immunotherapy.

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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. Cancer research. CAN Nicolas A, Cathelin D, Larmonier N, Fraszczak J, Puig P-E, Bouchot A, et al. The Journal of Immunology. Kim J, Yung BC, Kim WJ, Chen X. Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy.

Journal of Controlled Release. Molecular pharmaceutics. DOI: Tax calculation will be finalised at checkout. Licence this eBook for your library. Learn about institutional subscriptions. Table of contents 19 chapters Search within book Search.

Page 1 Navigate to page number of 2. Front Matter Pages i-xxiii. Molecular Cell Signaling by NO in Cancer Front Matter Pages Geller Pages Nitric Oxide and Genomic Stability Vasily A. Yakovlev Pages Targeting Hyponitroxia in Cancer Therapy Bryan Oronsky, Neil Oronsky, Michelle Lybeck, Gary Fanger, Jan Scicinski Pages Mechanisms of Nitric Oxide-Dependent Regulation of Tumor Invasion and Metastasis Aideen E.

Ryan, Amy J. Burke, Francis J. Giles, Francis J. Sullivan, Sharon A. Glynn Pages Role of Nitric Oxide in the Regulation of the Pro-tumourigenic Hypoxic Phenotype: From Instigation to Mitigation Lynne-Marie Postovit Pages S-Nitrosylation and Cancer Front Matter Pages Impacts of S-Nitrosylation in Cancer Tysha N.

Medeiros, Dana M. Jarigese, Melissa A. Edwards, Mark A. Brown Pages S-Nitrosylation in Cancer Cells: To Prevent or to Cause? Ali Bettaieb, Stéphanie Plenchette, Catherine Paul, Véronique Laurens, Sabrina Romagny, Jean-Fran ois Jeannin Pages The Emerging Role of Protein S-Nitrosylation in Cancer Metastasis Sudjit Luanpitpong, Yon Rojanasakul Pages Modulation of Anti-tumor Immune Responses by NO Front Matter Pages Nitric Oxide, Immunity and Cancer: From Pathogenesis to Therapy Hermes J.

Garbán Pages Regulation of Anti-Tumor Immune Responses Peter Siesjö Pages Nitric Oxide: Immune Modulation of Tumor Growth Naveena B. Janakiram, Chinthalapally V. Rao Pages Therapeutics and Overcoming Resistance Front Matter Pages Pivotal Role of Nitric Oxide in Chemo and Immuno Sensitization of Resistant Tumor Cells to Apoptosis Benjamin Bonavida Pages Emerging Role of NO-Mediated Therapeutics Cian M.

McCrudden, Helen O. McCarthy Pages Photodynamic Therapy and Nitric Oxide Emilia Della Pietra, Valentina Rapozzi Pages Regulation of Cell Death Signaling by Nitric Oxide in Cancer Cells Jordi Muntané, Francisco Gallardo-Chamizo, Sheila Pereira, Ángela M.

De los Santos, Ángeles Rodríguez-Hernández, Luís M. Marín et al. Pages