The Role Of Nitric Oxide In Cancer Development & it`s Therapy

Journal of Advanced Sciences and Engineering Technologies (2020) 3(1): 21-34

The Role Of Nitric Oxide In Cancer Development & it`s Therapy

Najlaa Qassim Muftin a,Asma Jameil Al-Lamei a  ,Suzanne Jubair ,Abdalla Raied Jabber ,Rasha Shakir Mahmood a,Mustasiryiah University, College of Science, Baghdad, Iraq b College of Pharmacy, University of Kerbala, Kerbala, Iraq

 

Abstract:The Nitric oxide is a free radical belongs to reactive nitrogen species, acts as a signal molecule in many physiological and pathological processes as well as plays a significant role in a variety of biological processes including its action as a regulator to programmed cell death (apoptosis). In addition to its role in tumor formation, proliferation, and metastasis, Nitric oxide has also been stated to have tumoricidal effects. Therefore this review deals with the effect of nitric oxide on different types of cancer and its use in cancer drugs

Keywords: Nitric oxide ,Cancer ,Therapy, Tumoricidal.

© 201x JASET, International Scholars and Researchers Association

DOI: http://dx.doi.org/10.32441/jaset.03. 01.02

Copyright © 2018 by author(s) and This work is licensed under the Creative
Commons Attribution International
License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

Download Full-text PDF

REFERENCES

[1]Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., LortetTieulent, J., & Jemal, A. (2015). Global cancer statistics, 2012. CA: a cancer journal for clinicians, 65(2), 87-108.

[2]Aiyengar, T. M., Chiranjeevi, P., & Rani, H. S. (2017). Role of Endothelial Nitric Oxide Synthase in Breast Cancer. Nitric Oxide Synthase: Simple Enzyme-Complex Roles, 179.

[3]Griendling, K. K., Sorescu, D., Lassègue, B., & Ushio-Fukai, M. (2000). Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arteriosclerosis, thrombosis, and vascular biology, 20(10), 2175-2183.

[4]Choudhari, S. K., Chaudhary, M., Bagde, S., Gadbail, A. R., & Joshi, V. (2013). Nitric oxide and cancer: a review. World journal of surgical oncology, 11(1), 118.

[5]Cheng, H., Wang, L., Mollica, M., Re, A. T., Wu, S., & Zuo, L. (2014). Nitric oxide in cancer metastasis. Cancer letters, 353(1), 1-7.

[6] Weller, R. (2012). Could the sun be good for your heart. TedxGlasgow March.

[7] Rőszer, T. (2012). The biology of subcellular nitric oxide. Springer Science & Business Media.

[8] Perez, K. M., & Laughon, M. (2015). Sildenafil in term and premature infants: a systematic review. Clinical therapeutics, 37(11), 2598-2607.

[9] Stryer, Lubert (1995). Biochemistry, 4th Edition. W.H. Freeman and Company. p. 732. ISBN 0-7167-2009-4.

[10] Lancaster, J. R. (2006). Nitroxidative, nitrosative, and nitrative stress: kinetic predictions of reactive nitrogen species chemistry under biological conditions. Chemical research in toxicology, 19(9), 1160-1174.

[11] Toledo, J. C., Bosworth, C. A., Hennon, S. W., Mahtani, H. A., Bergonia, H. A., & Lancaster, J. R. (2008). Nitric oxideinduced conversion of cellular chelatable iron into macromolecule-bound paramagnetic dinitrosyliron complexes. Journal of Biological Chemistry, 283(43), 28926-28933. [

12] Ford, P. C., & Lorkovic, I. M. (2002). Mechanistic aspects of the reactions of nitric oxide with transition-metal complexes. Chemical reviews, 102(4), 993-1018.

[13] Förstermann, U., Schmidt, H. H., Pollock, J. S., Sheng, H., Mitchell, J. A., Warner, T. D., … & Murad, F. (1991). Isoforms of nitric oxide synthase characterization and purification from different cell types. Biochemical pharmacology, 42(10), 1849-1857 Najlaa Qassim Muftin et al. / Journal of Advanced Sciences and Engineering Technologies 21-34 29

[14]Radomski, M. W., Jenkins, D. C., Holmes, L., & Moncada, S. (1991). Human colorectal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer research, 51(22), 6073- 6078.

[15] Zafirellis, K., Zachaki, A., Agrogiannis, G., & Gravani, K. (2010). Inducible nitric oxide synthase expression and its prognostic significance in colorectal cancer. Apmis, 118(2), 115-124. [16] Niu, X. J., Wang, Z. R., Wu, S. L., Geng, Z. M., Zhang, Y. F., & Qing, X. L. (2004). Relationship between inducible nitric oxide synthase expression and angiogenesis in primary gallbladder carcinoma tissue. World journal of gastroenterology, 10(5), 725.

[17] Lahiri, M., & Martin, J. H. J. (2009). Nitric oxide decreases motility and increases adhesion in human breast cancer cells. Oncology reports, 21(2), 275-281.

[18] Juang, S. H., Xie, K., Xu, L., Wang, Y., Yoneda, J., & Fidler, I. J. (1997). Use of retroviral vectors encoding murine inducible nitric oxide synthase gene to suppress tumorigenicity and cancer metastasis of murine melanoma. Cancer biotherapy & radiopharmaceuticals, 12(3), 167-175.

[19] Ambs, S., Merriam, W. G., Ogunfusika, M. O., Bennett, W. P., Ishibe, N., Hussain, S. P., … & Harris, C. C. (1998). p53 and vascular endothelial growth factor regulate tumor growth of NOS2- expressing human carcinoma cells. Nature medicine, 4(12), 1371.

[20] Cohen, R. A., Weisbrod, R. M., Gericke, M., Yaghoubi, M., Bierl, C., & Bolotina, V. M. (1999). Mechanism of nitric oxide– induced vasodilatation: refilling of intracellular stores by sarcoplasmic reticulum Ca2+ ATPase and inhibition of store-operated Ca2+ influx. Circulation research, 84(2), 210-219.

[21]Ying, L., & Hofseth, L. J. (2007). An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer research, 67(4), 1407- 1410.

[22] deRojas-Walker, T., Tamir, S., Ji, H., Wishnok, J. S., & Tannenbaum, S. R. (1995). Nitric oxide induces oxidative damage in addition to deamination in macrophage DNA. Chemical research in toxicology, 8(3), 473-477.

[23] Gal, A., & Wogan, G. N. (1996). Mutagenesis associated with nitric oxide production in transgenic SJL mice. Proceedings of the National Academy of Sciences, 93(26), 15102- 15107. [24] Wink, D. A., Vodovotz, Y., Laval, J., Laval, F., Dewhirst, M. W., & Mitchell, J. B. (1998). The multifaceted roles of nitric oxide in cancer. Carcinogenesis, 19(5), 711-721.

[25]Sun, Y. (1990). Free radicals, antioxidant enzymes, and carcinogenesis. Free Radical Biology and Medicine, 8(6), 583- 599.

[26]Wink, D. A., Kasprzak, K. S., Maragos, C. M., Elespuru, R. K., Misra, M., Dunams, T. M., … & Allen, J. S. (1991). DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science, 254(5034), 1001- 1003.

[27]Breast Cancer Awareness Month in October (World Health Organization 2012).

[28] Loibl, S., von Minckwitz, G., Weber, S., Sinn, H. P., SchiniKerth, V. B., Lobysheva, I., ,Nepveu F., Wolf G., Strebhardt K.& Kaufmann, M. (2002). 30 Journal of Advanced Sciences and Engineering Technologies (2020) Vo3 No1 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(6), 1191-1198.

[29]Alagöl, H., Erdem, E., Sancak, B., Turkmen, G., Camlibel, M., & Bugdayci, G. (1999). Nitric oxide biosynthesis and malondialdehyde levels in advanced breast cancer. Australian and New Zealand journal of surgery, 69(9), 647- 650.

[30] Thomsen, L. L., Miles, D. W., Happerfield, L., Bobrow, L. G., Knowles, R. G., & Moncada, S. (1995). Nitric oxide synthase activity in human breast cancer. British journal of cancer, 72(1), 41.

[31] Jadeski, L. C., Hum, K. O., Chakraborty, C., & Lala, P. K. (2000). Nitric oxide promotes murine mammary tumour growth and metastasis by stimulating tumour cell migration, invasiveness and angiogenesis. International journal of cancer, 86(1), 30-39.

[32] Avtandilyan, N., Javrushyan, H., Petrosyan, G., & Trchounian, A. (2018). The involvement of arginase and nitric oxide synthase in breast cancer development: arginase and NO synthase as therapeutic targets in cancer. BioMed research international, 2018.

[33] Mulshine, J. L., Cuttitta, F., Tockman, M. S., & De Luca, L. M. (2002). Lung cancer evolution to preinvasive management. Clinics in chest medicine, 23(1), 37-48.

[34]Bilello, K. S., Murin, S., & Matthay, R. A. (2002). Epidemiology, etiology, and prevention of lung cancer. Clinics in chest medicine, 23(1), 1-25.

[35] Masri, F. A., Comhair, S. A., Koeck, T., Xu, W., Janocha, A., Ghosh, S., … & Erzurum, S. C. (2005). Abnormalities in nitric oxide and its derivatives in lung cancer. American journal of respiratory and critical care medicine, 172(5), 597- 605.

[36]Wei, X. M., Wang, Q., Gao, S. J., & Sui, L. (2011). Relationship between nitric oxide in cervical microenvironment and different HPV types and effect on cervical cancer cells. Zhonghua fu chan ke za zhi, 46(4), 260-265.

[37] Chen, G. G., Lee, T. W., Xu, H., Yip, J. H., Li, M., Mok, T. S., & Yim, A. P. (2008). Increased inducible nitric oxide synthase in lung carcinoma of smokers. Cancer: Interdisciplinary International Journal of the American Cancer Society, 112(2), 372-381.

[38] Puhakka, A. R., Harju, T. H., Pääkkö, P. K., Soini, Y. M., & Kinnula, V. L. (2006). Nitric oxide synthases are associated with bronchial dysplasia. Lung Cancer, 51(3), 275-282.

[39]Forbes, T. A., Hopkins, L., Schneider, B., Lazarus, L., Leitenberg, D., Constant, S., Schwartz, A., Patierno, S., & Ceryak, S. (2012). Potential role of nitric oxide in chromium-induced lung carcinogenesis.

[40] Beckman, J. S., Ischiropoulos, H., Zhu, L., van der Woerd, M., Smith, C., Chen, J., … & Tsai, M. (1992). Kinetics of superoxide dismutase-and iron-catalyzed nitration of phenolics by peroxynitrite. Archives of Biochemistry and Biophysics, 298(2), 438-445.

[41]Haddad, I. Y., Pataki, G., Hu, P., Galliani, C., Beckman, J. S., & Matalon, S. (1994). Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. The Journal of clinical investigation, 94(6), 2407-2413. Najlaa Qassim Muftin et al. / Journal of Advanced Sciences and Engineering Technologies 21-34 31

[42 ]Masri, F. (2010). Role of nitric oxide and its metabolites as potential markers in lung cancer. Annals of thoracic medicine, 5(3), 123.

[43]Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005). Global cancer statistics, 2002. CA: a cancer journal for clinicians, 55(2), 74-108.

[44]Zur Hausen, H. (2002). Papillomaviruses and cancer: from basic studies to clinical application. Nature reviews cancer, 2(5), 342.

[45] Benencia, F., Gamba, G., Cavalieri, H., Courreges, M. C., Benedetti, R., Villamil, S. M., & Massouh, E. J. (2003). Nitric oxide and HSV vaginal infection in BALB/c mice. Virology, 309(1), 75-84.

[46] Chang, K., & Zhang, L. (2008). Steroid hormones and uterine vascular adaptation to pregnancy. Reproductive Sciences, 15(4), 336-348.

[47] Naidu, M. S. K., Suryakar, A. N., Swami, S. C., Katkam, R. V., & Kumbar, K. M. (2007). Oxidative stress and antioxidant status in cervical cancer patients. Indian Journal of Clinical Biochemistry, 22(2), 140-144.

[48] Beevi, S. S., Rasheed, M. H., & Geetha, A. (2007). Evidence of oxidative and nitrosative stress in patients with cervical squamous cell carcinoma. Clinica Chimica Acta, 375(1-2), 119-123.

[49]Hiraku, Y., Tabata, T., Ma, N., Murata, M., Ding, X., & Kawanishi, S. (2007). Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection. Cancer science, 98(7), 964- 972.

[50] Tavares-Murta, B. M., de Resende, A. D., Cunha, F. Q., & Murta, E. F. C. (2008). Local profile of cytokines and nitric oxide in patients with bacterial vaginosis and cervical intraepithelial neoplasia. European Journal of Obstetrics & Gynecology and Reproductive Biology, 138(1), 93-99.

[51] Correa, P., Piazuelo, M. B., & Camargo, M. C. (2004). The future of gastric cancer prevention. Gastric cancer, 7(1), 9-16.

[52]Calatayud, S., Barrachina, D., & Esplugues, J. V. (2001). Nitric oxide: relation to integrity, injury, and healing of the gastric mucosa. Microscopy Research and Technique, 53(5), 325-335.

[53] Yagihashi, N., Kasajima, H., Sugai, S., Matsumoto, K., Ebina, Y., Morita, T., … & Yagihashi, S. (2000). Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Archiv, 436(2), 109-114.

[54]Feng, C. W., Wang, L. D., Jiao, L. H., Liu, B., Zheng, S., & Xie, X. J. (2002). Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: correlation with clinical features. BMC cancer, 2(1), 8.

[55]Correa, P. (1992). Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer research, 52(24), 6735-6740.

[56]You, W. C., Blot, W. J., Li, J. Y., Chang, Y. S., Jin, M. L., Kneller, R., Zhang L, Han, Z.X., Zeng, X.R., Liu, W.D., Zhao, L., Correa, P., Fraumeni, J.F., Xu ,G.W. (1993). Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer research, 53(6), 1317- 1321.

[57]Broholm, H., Rubin, I., Kruse, A., Braendstrup, O., Schmidt, K., Skriver, E. B., & Lauritzen, M. (2003). Nitric oxide synthase expression and enzymatic 32 Journal of Advanced Sciences and Engineering Technologies (2020) Vo3 No1 activity in human brain tumors. Clinical neuropathology, 22(6), 273-281.

[58] Cobbs, C. S., Brenman, J. E., Aldape, K. D., Bredt, D. S., & Israel, M. A. (1995). Expression of nitric oxide synthase in human central nervous system tumors. Cancer Research, 55(4), 727- 730.

[59]Nagpal, J. K., & Das, B. R. (2003). Oral cancer: reviewing the present understanding of its molecular mechanism and exploring the future directions for its effective management. Oral oncology, 39(3), 213- 221.

[60]Patel, B. P., Rawal, U. M., Rawal, R. M., Shukla, S. N., & Patel, P. S. (2008). Tobacco, antioxidant enzymes, oxidative stress, and genetic susceptibility in oral cancer. American journal of clinical oncology, 31(5), 454-459.

[61]Nair, U., Bartsch, H., & Nair, J. (2004). Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms. Mutagenesis, 19(4), 251- 262.

[62] Rasheed, M. H., Beevi, S. S., & Geetha, A. (2007). Enhanced lipid peroxidation and nitric oxide products with deranged antioxidant status in patients with head and neck squamous cell carcinoma. Oral oncology, 43(4), 333-338.

[63] Patel, J. B., Shah, F. D., Shukla, S. N., Shah, P. M., & Patel, P. S. (2009). Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer. Journal of cancer research and therapeutics, 5(4), 247.

[64] Korde, S. D., Basak, A., Chaudhary, M., Goyal, M., & Vagga, A. (2011). Enhanced nitrosative and oxidative stress with decreased total antioxidant capacity in patients with oral precancer and oral squamous cell carcinoma. Oncology, 80(5-6), 382-389.

[65] Hashibe, M., Brennan, P., Benhamou, S., Castellsague, X., Chen, C., Curado, M. P., Dal Maso, L., Daudt, A.W., Fabianova, E., Fernandez, L., Wünsch-Filho, V., Franceschi, S., Hayes, R.B., Herrero, R., Koifman ,S., La Vecchia, C., Lazarus, P., Levi, F.,Mates, D., Matos, E., Menezes, A., Muscat, J., Eluf-Neto, J., Olshan, A.F., Rudnai, P.,Schwartz, S.M., Smith, E., Sturgis, E.M., Szeszenia-Dabrowska, N., Talamini, R., Wei,, Q., Winn ,D.M., Zaridze, D., Zatonski, W., Zhang, Z., Berthiller, J., Boffetta, P .(2007). Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Journal of the National Cancer Institute, 99(10), 777-789.

[66]Cooper, R. G., & Magwere, T. (2008). Mini-review article nitric oxide-mediated pathogenesis during nicotine and alcohol consumption. Indian J Physiol Pharmacol, 52(1), 11-18. [67]Shang, Z. J., Li, J. R., & Li, Z. B. (2002). Effects of exogenous nitric oxide on oral squamous cell carcinoma: an in vitro study. Journal of oral and maxillofacial surgery, 60(8), 905-910.

[68] Li, L., Kilbourn, R. G., Adams, J., & Fidler, I. J. (1991). Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells. Cancer research, 51(10), 2531-2535.

[69] Shang, Z. J., & Li, J. R. (2005). Expression of endothelial nitric oxide synthase and vascular endothelial growth Najlaa Qassim Muftin et al. / Journal of Advanced Sciences and Engineering Technologies 21-34 33 factor in oral squamous cell carcinoma: its correlation with angiogenesis and disease progression. Journal of oral pathology & medicine, 34(3), 134-139.

[70] Lechner, M., Lirk, P., & Rieder, J. (2005, August). Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. In Seminars in cancer biology (Vol. 15, No. 4, pp. 277-289). Academic Press.

[71] Lepoivre, M., Flaman, J. M., & Henry, Y. (1992). Early loss of the tyrosyl radical in ribonucleotide reductase of adenocarcinoma cells producing nitric oxide. Journal of Biological Chemistry, 267(32), 22994-23000.

[72]Choi, B. M., Pae, H. O., Jang, S. I., Kim, Y. M., & Chung, H. T. (2002). Nitric oxide as a pro-apoptotic as well as antiapoptotic modulator. BMB Reports, 35(1), 116-126.

[73]Aranda, E., Lopez-Pedrera, C., R De La Haba-Rodriguez, J., & Rodriguez-Ariza, A. (2012). Nitric oxide and cancer: the emerging role of S-nitrosylation. Current molecular medicine, 12(1), 50-67.

[74] Baritaki, S., Huerta-Yepez, S., Sahakyan, A., Karagiannides, I., Bakirtzi, K., Jazirehi, A., & Bonavida, B. (2010). Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP. Cell cycle, 9(24), 4931-4940.

[75]Bonavida, B., & Baritaki, S. (2012). Inhibition of epithelial-to-mesenchymal transition (EMT) in cancer by nitric oxide: pivotal roles of nitrosylation of NF-κB, YY1 and Snail. In Forum on immunopathological diseases and therapeutics (Vol. 3, No. 2). Begel House Inc..

[76] Moncada, S. R. M. J. (1991). Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol rev, 43, 109- 142.

[77] Zhao, S. F., Tong, X. Y., & Zhu, F. D. (2005). Nitric oxide induces oral squamous cell carcinoma cells apoptosis with p53 accumulation. Oral oncology, 41(8), 785-790.

[78] Brennan, P. A., Palacios-Callender, M., Umar, T., Tant, S., & Langdon, J. D. (2002). Expression of type 2 nitric oxide synthase and p21 in oral squamous cell carcinoma. International journal of oral and maxillofacial surgery, 31(2), 200- 205.

[79] Gallo, O., Fini-Storchi, I., Vergari, W. A., Masini, E., Morbidelli, L., Ziche, M., & Franchi, A. (1998). Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. JNCI: Journal of the National Cancer Institute, 90(8), 587- 596.

[80] Burke, A. J., Sullivan, F. J., Giles, F. J., & Glynn, S. A. (2013). The yin and yang of nitric oxide in cancer progression. Carcinogenesis, 34(3), 503- 512.

[81]Ridnour, L. A., Thomas, D. D., Switzer, C., Flores-Santana, W., Isenberg, J. S., Ambs, S., Roberts, D.D., & Wink, D. A. (2008). Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric oxide, 19(2), 73-76.

[82] Huerta, S. (2015). Nitric oxide for cancer therapy. Future science OA, 1(1). [

83]Coulter, J. A., McCarthy, H. O., Xiang, J., Roedl, W., Wagner, E., Robson, T., & Hirst, D. G. (2008). Nitric oxide—a novel therapeutic for cancer. Nitric oxide, 19(2), 192-198.

[84] Burgaud, J. L., Ongini, E., & Del Soldato, P. I. E. R. O. (2002). Nitric oxide 34 Journal of Advanced Sciences and Engineering Technologies (2020) Vo3 No1 releasing drugs: a novel class of effective and safe therapeutic agents. Annals of the New York Academy of Sciences, 962(1), 360-371.

[85] Stolfi, C., De Simone, V., Pallone, F., & Monteleone, G. (2013). Mechanisms of action of non-steroidal anti-inflammatory drugs (NSAIDs) and mesalazine in the chemoprevention of colorectal cancer. International journal of molecular sciences, 14(9), 17972-17985.

[86]Domingo, E., Church, D. N., Sieber, O., Ramamoorthy, R., Yanagisawa, Y., Johnstone, E., Davidson, B., Kerr, D.J., Tomlinson, I.P.M. & Midgley, R. (2013). Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol, 31(34), 4297-4305.

[87] Cheng, H., Mollica, M. Y., Lee, S. H., Wang, L., Velázquez-Martínez, C. A., & Wu, S. (2012). Effects of nitric oxidereleasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion. Toxicology and applied pharmacology, 264(2), 161-166.

[88]Williams, J. L., Borgo, S., Hasan, I., Castillo, E., Traganos, F., & Rigas, B. (2001). Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention. Cancer Research, 61(8), 3285-3289.

[89]Kashfi, K., Rayyan, Y., Qiao, L. L., Williams, J. L., Chen, J., del Soldato, P., Traganos ,F. & Rigas, B. (2002). Nitric oxide-donating nonsteroidal antiinflammatory drugs inhibit the growth of various cultured human cancer cells: evidence of a tissue type-independent effect. Journal of Pharmacology and Experimental Therapeutics, 303(3), 1273- 1282.

[90] Cooper, R. G., & Magwere, T. (2008). Mini-review article nitric oxide-mediated pathogenesis during nicotine and alcohol consumption. Indian J Physiol Pharmacol, 52(1), 11-18.

[91] Brüne, B. (2003). Nitric oxide: NO apoptosis or turning it ON?. Cell death and differentiation, 10(8), 864.