The Role of Nitric Oxide from Neurological Disease to Cancer

  • Ahmed Maher
  • Mohamed F. Abdel Rahman
  • Mohamed Z. GadEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1007)


Until the beginning of the 1980s, nitric oxide (NO) was just a toxic molecule of a lengthy list of environmental pollutants such as cigarette smoke and smog. In fact, NO had a very bad reputation of being destroyer of ozone, suspected carcinogen and precursor of acid rain. However, by the early 1990s it was well recognized by the medical research community. Over the last two decades, the picture has been totally changed. Diverse lines of evidence have converged to show that this sometime poison is a fundamental player in the everyday business of the human body. NO activity was probed in the brain, arteries, immune system, liver, pancreas, uterus, peripheral nerves, lungs, and almost every system in the human body. NO is a major player in the cardiovascular system as it is involved in regulating blood pressure. In the CNS, it is involved in memory formation and the regulation of cerebral blood flow to ensure adequate supply of blood to the brain. Because NO is involved in many pathways, it has a role in several diseases related to modern life as hypertension, coronary heart diseases, Alzheimer’s Disease, stroke and cancer. This chapter focuses on the discussion of the role of NO in neurological diseases and cancer and how can this Janus-faced molecule play a role in the pathology and personalized treatment of these diseases.


Nitric oxide (NO) NO signal transduction CNS Neurodegeneration disorders Cancer NOS expression NO-targeted therapy 


  1. 1.
    Moncada S, Palmer RM, Higgs EA (1988) The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 12:365–372PubMedCrossRefGoogle Scholar
  2. 2.
    Ignarro LJ (1989) Endothelium-derived nitric oxide: actions and properties. FASEB J 3:31–36PubMedGoogle Scholar
  3. 3.
    Murad F (2011) Nitric oxide: the coming of the second messenger. Rambam Maimonides Med J 2:e0038PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Thomas DD (2015) Breathing new life into nitric oxide signaling: a brief overview of the interplay between oxygen and nitric oxide. Redox Biol 5:225–233PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837PubMedCrossRefGoogle Scholar
  6. 6.
    Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Bian K, Murad F (2014) What is next in nitric oxide research? From cardiovascular system to cancer biology. Nitric Oxide 43:3–7PubMedCrossRefGoogle Scholar
  8. 8.
    El-Sehemy A, Postovit L-M, Fu Y (2016) Nitric oxide signaling in human ovarian cancer: a potential therapeutic target. Nitric Oxide Biol Chem 54:30–37CrossRefGoogle Scholar
  9. 9.
    Adams L, Franco MC, Estevez AG (2015) Reactive nitrogen species in cellular signaling. Exp Biol Med (Maywood) 240:711–717CrossRefGoogle Scholar
  10. 10.
    WHO (2006) Public health challenges WHO Library Cataloguing-in-Publication Data. World Health OrganizationGoogle Scholar
  11. 11.
    Thakur KT et al (2016) Chapter 5 Neurological disorders. Ment Neurol Subst Use Disord Dis Control Priorities, Third Ed 4:265Google Scholar
  12. 12.
    Jiang Z et al (2014) Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia. PLoS One 9:e93134PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kudlow P, Cha DS, Carvalho AF, McIntyre RS (2016) Nitric oxide and major depressive disorder: pathophysiology and treatment implications. Curr Mol Med 16:206–215PubMedCrossRefGoogle Scholar
  14. 14.
    Calabrese V et al (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775PubMedCrossRefGoogle Scholar
  15. 15.
    Benarroch EE (2011) Nitric oxide: a pleiotropic signal in the nervous system. Neurology 77:1568–1576PubMedCrossRefGoogle Scholar
  16. 16.
    Pierrefiche O, Naassila M (2014) Endogenous nitric oxide but not exogenous no-donor S-nitroprussiate facilitates NMDA excitation in spontaneous rhythmic neonatal rat brainstem slice. Brain Res 1543:9–16PubMedCrossRefGoogle Scholar
  17. 17.
    Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51–68PubMedCrossRefGoogle Scholar
  18. 18.
    Dash PR et al (2007) Fas ligand-induced apoptosis is regulated by nitric oxide through the inhibition of fas receptor clustering and the nitrosylation of protein kinase Cε. Exp Cell Res 313:3421–3431PubMedCrossRefGoogle Scholar
  19. 19.
    Benarroch EE (2011) NMDA receptors: recent insights and clinical correlations. Neurology 76:1750–1757PubMedCrossRefGoogle Scholar
  20. 20.
    Um H-C, Jang J-H, Kim D-H, Lee C, Surh Y-J (2011) Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells. Nitric Oxide 25:161–168PubMedCrossRefGoogle Scholar
  21. 21.
    Knott AB, Bossy-Wetzel E (2009) Nitric oxide in halth and disease of the nervous system. Antioxid Redox Signal 11:541–553PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Nakamura T, Lipton SA (2011) Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death Differ 18:1478–1486PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Linares D et al (2006) Neuronal nitric oxide synthase plays a key role in CNS demyelination. J Neurosci 26:12672–12681PubMedCrossRefGoogle Scholar
  24. 24.
    Calabrese V et al (2009) Nitric oxide in cell survival: a janus molecule. Antioxid Redox Signal 11:2717–2739PubMedCrossRefGoogle Scholar
  25. 25.
    Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509CrossRefGoogle Scholar
  26. 26.
    Rivera DS, Inestrosa NC, Bozinovic F (2016) On cognitive ecology and the environmental factors that promote Alzheimer disease: lessons from Octodon degus (Rodentia: Octodontidae). Biol Res 49:10PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s Disease. N Engl J Med 362:329–344PubMedCrossRefGoogle Scholar
  28. 28.
    Berridge MJ (2014) Calcium regulation of neural rhythms, memory and Alzheimer’s disease. J Physiol 592:281–293PubMedCrossRefGoogle Scholar
  29. 29.
    Iqbal K, Liu F, Gong C-X (2014) Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol 88:631–639PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bird TD (2008) Genetic aspects of Alzheimer disease. Genet Med 10:231–239PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Holmes C et al (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Balez R, Ooi L (2016) Getting to NO Alzheimer’s disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxidative Med Cell Longev 2016:3806157CrossRefGoogle Scholar
  33. 33.
    Guo H et al (2017) FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology 116:260–269PubMedCrossRefGoogle Scholar
  34. 34.
    Franco MC et al (2015) Nitration of Hsp90 on tyrosine 33 regulates mitochondrial metabolism. J Biol Chem 290:19055–19066PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Guivernau B et al (2016) Amyloid- peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicity. J Neurosci 36:11693–11703PubMedCrossRefGoogle Scholar
  36. 36.
    Ryan SD et al (2013) Isogenic human iPSC parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 155:1351–1364PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Nakamura T et al (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99–108PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Xu B et al (2014) Alpha-synuclein oligomerization in manganese-induced nerve cell injury in brain slices: a role of NO-mediated S-nitrosylation of protein disulfide isomerase. Mol Neurobiol 50:1098–1110PubMedCrossRefGoogle Scholar
  39. 39.
    Uehara T et al (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441:513–517PubMedCrossRefGoogle Scholar
  40. 40.
    Benskey MJ, Perez RG, Manfredsson FP (2016) The contribution of alpha synuclein to neuronal survival and function – implications for Parkinson’s disease. J Neurochem 137:331–359PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Cho D-H, Nakamura T, Lipton SA (2010) Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci 67:3435–3447PubMedCrossRefGoogle Scholar
  42. 42.
    Haun F et al (2013) S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in huntington’s disease. Antioxid Redox Signal 19:1173–1184PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Qu J et al (2011) S-nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by -amyloid peptide. Proc Natl Acad Sci 108:14330–14335PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Nakamura T, Cho D-H, Lipton SA (2012) Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases. Exp Neurol 238:12–21PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bae B-I et al (2006) Mutant huntingtin: nuclear translocation and cytotoxicity mediated by GAPDH. Proc Natl Acad Sci 103:3405–3409PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Wu H et al (2014) Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. Int J Biol Sci 10:1072–1083PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Tsang AHK et al (2009) S-nitrosylation of XIAP compromises neuronal survival in Parkinson’s disease. Proc Natl Acad Sci U S A 106:4900–4905PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Nakamura T et al (2010) Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Mol Cell 39:184–195PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Nakamura T, Lipton SA (2016) Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases. Trends Pharmacol Sci 37:73–84PubMedCrossRefGoogle Scholar
  50. 50.
    Okamoto S, Lipton SA (2015) S-nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588–1593PubMedCrossRefGoogle Scholar
  51. 51.
    Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KTS (2015) The role of the nitric oxide pathway in brain injury and its treatment – from bench to bedside. Exp Neurol 263:235–243PubMedCrossRefGoogle Scholar
  52. 52.
    Attwell D et al (2010) Glial and neuronal control of brain blood flow. Nature 468:232–243PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Minamino T et al (1998) Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation 98:1721–1727PubMedCrossRefGoogle Scholar
  54. 54.
    Sabri M et al (2012) Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience 224:26–37PubMedCrossRefGoogle Scholar
  55. 55.
    Dreier JP, Reiffurth C (2015) The stroke-migraine depolarization continuum. Neuron 86:902–922PubMedCrossRefGoogle Scholar
  56. 56.
    Kim JY, Park J, Chang JY, Kim S-H, Lee JE (2016) Inflammation after ischemic stroke: the role of leukocytes and glial cells. Exp Neurobiol 25:241–251PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Garcia-Bonilla L et al (2014) Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 193:2531–2537PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ridnour LA et al (2006) The biphasic nature of nitric oxide responses in tumor biology. Antioxid Redox Signal 8:1329–1337PubMedCrossRefGoogle Scholar
  59. 59.
    Martínez MC, Andriantsitohaina R (2009) Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid Redox Signal 11:669–702PubMedCrossRefGoogle Scholar
  60. 60.
    Oronsky B, Fanger GR, Oronsky N, Knox S, Scicinski J (2014) The implications of hyponitroxia in cancer. Transl Oncol 7:167–173PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lechner M, Lirk P, Rieder J (2005) Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol 15:277–289PubMedCrossRefGoogle Scholar
  62. 62.
    Ridnour LA et al (2008) Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 19:73–76PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Vannini F, Kashfi K, Nath N (2015) The dual role of iNOS in cancer. Redox Biol 6:334–343PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Criss WE, Murad F, Kimura H, Morris HP (1976) Properties of guanylate cyclase in adult rat liver and several Morris hepatomas. Biochim Biophys Acta Enzymol 445:500–508CrossRefGoogle Scholar
  65. 65.
    Zhu H et al (2011) Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma. Mol Pharmacol 80:1076PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Singh SK et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  67. 67.
    Albina JE, Cui S, Mateo RB, Reichner JS (1993) Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 150:5080–5085PubMedGoogle Scholar
  68. 68.
    Messmer UK, Brüne B (1996) Nitric oxide-induced apoptosis: p53-dependent and p53-independent signalling pathways. Biochem J 319:299–305PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Chipuk JE et al (2004) Direct activation of bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science (80-.) 303:1010–1014CrossRefGoogle Scholar
  70. 70.
    Mihara M et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577–590PubMedCrossRefGoogle Scholar
  71. 71.
    Tovar C et al (2013) MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 73:2587–2597PubMedCrossRefGoogle Scholar
  72. 72.
    Lujambio A et al (2013) Non-cell-autonomous tumor suppression by p53. Cell 153:449–460PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Strasser A, Harris AW, Jacks T, Cory S (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329–339PubMedCrossRefGoogle Scholar
  74. 74.
    Bicknell GR, Snowden RT, Cohen GM (1994) Formation of high molecular mass DNA fragments is a marker of apoptosis in the human leukaemic cell line, U937. J Cell Sci 107:2483PubMedGoogle Scholar
  75. 75.
    Xu W, Lliu LZ, Loizidou M, Ahmed M, Charles IG (2002) The role of nitric oxide in cancer. Cell Res 12:311–320PubMedCrossRefGoogle Scholar
  76. 76.
    Jaiswal M, LaRusso N, Burgart L, Gores G (2000) Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60(1):184–190Google Scholar
  77. 77.
    Mocellin S, Bronte V, Nitti D (2007) Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Med Res Rev 27:317–352PubMedCrossRefGoogle Scholar
  78. 78.
    Thomsen LL et al (1995) Nitric oxide synthase activity in human breast cancer. Br J Cancer 72:41–44PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Reveneau S et al (1999) Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors. Lab Investig 79:1215–1225PubMedGoogle Scholar
  80. 80.
    Vakkala M et al (2000) Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas. Clin Cancer Res 6:2408–2416PubMedGoogle Scholar
  81. 81.
    Loibl S et al (2002) Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy. Cancer 95:1191–1198PubMedCrossRefGoogle Scholar
  82. 82.
    Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918PubMedCrossRefGoogle Scholar
  83. 83.
    Lim K-H, Ancrile BB, Kashatus DF, Counter CM (2008) Tumour maintenance is mediated by eNOS. Nature 452:646–649PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2015) Caveolae and signalling in cancer. Nat Rev Cancer 15:225–237PubMedCrossRefGoogle Scholar
  85. 85.
    Feron O, Saldana F, Michel JB, Michel T (1998) The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem 273:3125–3128PubMedCrossRefGoogle Scholar
  86. 86.
    Cleeter MWJ, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AHV (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. FEBS Lett 345:50–54PubMedCrossRefGoogle Scholar
  87. 87.
    Martinez-Outschoorn UE, Lisanti MP, Sotgia F (2014) Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin Cancer Biol 25:47–60PubMedCrossRefGoogle Scholar
  88. 88.
    Witkiewicz AK et al (2009) An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 174:2023–2034PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Sloan EK et al (2009) Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol 174:2035–2043PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Goetz JG et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146:148–163PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Ayala G et al (2013) Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. J Pathol 231:77–87PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Zhao X et al (2013) Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS One 8:e59102PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kim YM, Bombeck CA, Billiar TR (1999) Nitric oxide as a bifunctional regulator of apoptosis. Circ Res 84:253–256PubMedCrossRefGoogle Scholar
  94. 94.
    Choi B-M, Pae H-O, Jang SII, Kim Y-M, Chung H-T (2002) Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator endogenous NO production and NO donors. J Biochem Mol Biol 35:116–126PubMedGoogle Scholar
  95. 95.
    Genaro AM, Hortelano S, Alvarez A, Martínez C, Boscá L (1995) Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. J Clin Invest 95:1884–1890PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Li J, Yang S, Billiar TR (2000) Cyclic nucleotides suppress tumor necrosis factor alpha-mediated apoptosis by inhibiting caspase activation and cytochrome c release in primary hepatocytes via a mechanism independent of Akt activation. J Biol Chem 275:13026–13034PubMedCrossRefGoogle Scholar
  97. 97.
    Kim Y et al (2000) Nitric oxide prevents tumor necrosis factor α–induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S-nitrosylation of caspase-8. Hepatology 32:770–778PubMedCrossRefGoogle Scholar
  98. 98.
    Kim YM, Talanian RV, Billiar TR (1997) Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J Biol Chem 272:31138–31148PubMedCrossRefGoogle Scholar
  99. 99.
    Ceneviva GD et al (1998) Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells. Am J Phys 275:L717–L728Google Scholar
  100. 100.
    Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS (1994) Nitric oxide produced by human B lymphocytes inhibits apoptosis and epstein-barr virus reactivation. Cell 79:1137–1146PubMedCrossRefGoogle Scholar
  101. 101.
    Hussain AR et al (2015) Xiap over-expression is a poor prognostic marker in breast cancer and can be targeted to induce efficient apoptosis. Cancer Res 75Google Scholar
  102. 102.
    Ji J et al (2015) XIAP maintains the characteristics of cancer stem cells and is a therapeutic target in nasopharyngeal carcinoma. Cancer Res 75Google Scholar
  103. 103.
    Gu L et al (2016) Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment. Cancer Cell 30:623–636PubMedCrossRefGoogle Scholar
  104. 104.
    Yang J et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132PubMedCrossRefGoogle Scholar
  105. 105.
    Kim YM, Chung HT, Simmons RL, Billiar TR (2000) Cellular non-heme iron content is a determinant of nitric oxide-mediated apoptosis, necrosis, and caspase inhibition. J Biol Chem 275:10954–10961PubMedCrossRefGoogle Scholar
  106. 106.
    Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMedCrossRefGoogle Scholar
  107. 107.
    Kim Y-M, Bergonia H, Lancaster JR (1995) Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett 374:228–232PubMedCrossRefGoogle Scholar
  108. 108.
    Kim YM, de Vera ME, Watkins SC, Billiar TR (1997) Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biol Chem 272:1402–1411PubMedCrossRefGoogle Scholar
  109. 109.
    Liu D et al (2000) Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-). Diabetes 49:1116–1122PubMedCrossRefGoogle Scholar
  110. 110.
    Rössig L et al (2000) Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis. J Biol Chem 275:25502–25507PubMedCrossRefGoogle Scholar
  111. 111.
    Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V (2013) Nitric oxide and cancer: a review. World J Surg Oncol 11:118PubMedCrossRefGoogle Scholar
  112. 112.
    Ziche M, Morbidelli L (2000) Nitric oxide and angiogenesis. J Neuro-Oncol 50:139–148CrossRefGoogle Scholar
  113. 113.
    Jenkins DC et al (1995) Roles of nitric oxide in tumor growth. Proc Natl Acad Sci U S A 92:4392–4396PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Morbidelli L, Donnini S, Ziche M (2004) Role of nitric oxide in tumor angiogenesis. Cancer Treat Res 117:155–167PubMedCrossRefGoogle Scholar
  115. 115.
    Gallo O et al (1998) Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst 90:587–596PubMedCrossRefGoogle Scholar
  116. 116.
    Franchi A et al (2002) Inducible nitric oxide synthase expression in laryngeal neoplasia: correlation with angiogenesis. Head Neck 24:16–23PubMedCrossRefGoogle Scholar
  117. 117.
    Hoeben A et al (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56.Google Scholar
  118. 118.
    Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313:17–29PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Sappayatosok K et al (2009) Expression of pro-inflammatory protein, iNOS, VEGF and COX-2 in oral squamous cell carcinoma (OSCC), relationship with angiogenesis and their clinico-pathological correlation. Med Oral Patol Oral Cir Bucal 14:E319–E324PubMedGoogle Scholar
  120. 120.
    Medeiros RM et al (2002) Outcome in prostate cancer: association with endothelial nitric oxide synthase Glu-Asp298 polymorphism at exon 7. Clin Cancer Res 8:3433–3437PubMedGoogle Scholar
  121. 121.
    Ghilardi G et al (2003) Vascular invasion in human breast cancer is correlated to T-->786C polymorphism of NOS3 gene. Nitric Oxide Biol Chem 9:118–122CrossRefGoogle Scholar
  122. 122.
    Tatemichi M et al (2005) Increased risk of intestinal type of gastric adenocarcinoma in Japanese women associated with long forms of CCTTT pentanucleotide repeat in the inducible nitric oxide synthase promoter. Cancer Lett 217:197–202PubMedCrossRefGoogle Scholar
  123. 123.
    Marangoni K, Araújo TG, Neves AF, Goulart LR (2008) The -786T>C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression. BMC Cancer 8:273PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Lee K-M et al (2009) Nitric oxide synthase gene polymorphisms and prostate cancer risk. Carcinogenesis 30:621–625PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Gao X, Wang J, Wang W, Wang M, Zhang J (2015) eNOS genetic polymorphisms and cancer risk a meta-analysis and a case–control study of breast cancer. Medicine (Baltimore) 94:1–10Google Scholar
  126. 126.
    Jiao J, Wu J, Huang D, Liu L (2015) Lack of association of the iNOS gene polymorphism with risk of cancer: a systematic review and Meta-Analysis. Sci Rep 5:9889PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Koppula S, Kumar H, Kim IS, Choi D-K (2012) Reactive oxygen species and inhibitors of inflammatory enzymes, NADPH oxidase, and iNOS in experimental models of Parkinson’s disease. Mediat Inflamm 2012:823902CrossRefGoogle Scholar
  128. 128.
    Godínez-Rubí M, Rojas-Mayorquín AE, Ortuño-Sahagún D (2013) Nitric oxide donors as neuroprotective agents after an ischemic stroke-related inflammatory reaction. Oxidative Med Cell Longev 2013:297357CrossRefGoogle Scholar
  129. 129.
    Atochin DN et al (2016) A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia–reperfusion injury in mice. Neurosci Lett 618:45–49PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Woodhouse L et al (2015) Effect of hyperacute administration (within 6 hours) of transdermal glyceryl trinitrate, a nitric oxide donor, on outcome after stroke. Stroke 46:3194–3201PubMedCrossRefGoogle Scholar
  131. 131.
    Hickok JR, Thomas DD (2010) Nitric oxide and cancer therapy: the emperor has NO clothes. Curr Pharm Des 16:381–391PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Kanayama N, Yamaguchi K, Nagasaki Y (2010) PEGylated polymer micelle-based nitric oxide (NO) photodonor with NO-mediated antitumor activity. Chem Lett 39:1008–1009CrossRefGoogle Scholar
  133. 133.
    Kim J, Yung BC, Kim WJ, Chen X (2016) Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy. J Control Release. doi: 10.1016/j.jconrel.2016.12.026
  134. 134.
    Chakrapani H et al (2008) Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: structural analogues of PABA/NO, an anti-cancer lead compound. Bioorg Med Chem 16:2657–2664PubMedCrossRefGoogle Scholar
  135. 135.
    Kiziltepe T et al (2007) JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood 110:709–718PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Dong R et al (2017) Effects of JS-K, a novel anti-cancer nitric oxide prodrug, on gene expression in human hepatoma Hep3B cells. Biomed Pharmacother 88:367–373. doi: 10.1016/j.biopha.2017.01.080
  137. 137.
    Liu J et al (2009) Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells. Genomics 94:32–38PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Hagos GK et al (2007) Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Mol Cancer Ther 6:2230–2239PubMedCrossRefGoogle Scholar
  139. 139.
    Gao J, Liu X, Rigas B (2005) Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. Proc Natl Acad Sci 102:17207–17212PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Aliev G et al (2013) Link between cancer and Alzheimer disease via oxidative stress induced by nitric oxide-dependent mitochondrial DNA overproliferation and deletion. Oxidative Med Cell Longev 2013:962984CrossRefGoogle Scholar
  141. 141.
    Stewart B, Wild CP (eds) (2014). International Agency for Research on Cancer, W World Cancer Rep 2014Google Scholar
  142. 142.
    International Agency for Research on Cancer and Cancer Research UK (2014) World cancer factsheet.Google Scholar
  143. 143.
    Fidler I, Timeline J (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458PubMedCrossRefGoogle Scholar
  144. 144.
    Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (2006) Angiogenesis in cancer. Vasc Health Risk Manag 2:213–219PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Ahmed Maher
    • 1
  • Mohamed F. Abdel Rahman
    • 1
  • Mohamed Z. Gad
    • 2
    Email author
  1. 1.Biochemistry Department, Faculty of PharmacyOctober University for Modern Sciences and Arts (MSA)CairoEgypt
  2. 2.Clinical Biochemistry Unit, Faculty of Pharmacy & BiotechnologyGerman University in Cairo (GUC)CairoEgypt

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