Role of nitric oxide in pathogenesis of tumor growth and its possible application in cancer treatment

Abstract

Summary. In this review, the role of nitric oxide (NO) in the pathogenesis of the tumor growth and possibilities of its application in the treatment of cancer patients are analyzed. NO is one of the most important mediators of physiological processes being involved in the regulation of practically all body functions in health and disease. The role of NO in the development of many pathological conditions has been extensively studied and debated in recent years. Today it is clear that NO in relation to malignant tumors may exhibit a dual activity — can stimulate tumor growth and cause an opposite antitumor effect. Effects of NO are mostly dependent on its concentration. At low concentrations, NO could inhibit apoptosis and cause mutations that potentially lead to the formation of malignant growth loci. However, a high concentration of NO appears to be detrimental to malignant cells, in particular under conditions of simultaneous exposure to ionizing radiation. In humans, the inducible NO synthase (iNOS, type II) is the most powerful form of NO synthases (NOS) and has the ability to synthesize large amounts of NO for a long time and exert a protective function. iNOS is expressed in macrophages, monocytes, neutrophils, fibroblasts, hepatocytes, and other cell types. In tissue of malignant tumors, the macrophagal iNOS is the main form. Experimental data provide an evidence that activated macrophages and leukocytes, which are the part of peritumorous inflammatory infiltrate, can provide radiosensitization of tumors by direct synthesis of NO and indirectly — through the secretion of cytokines stimulating iNOS activity in cancer cells. Such approach could be useful for the development of new schemes and methods of anticancer therapy based on the activation of endogenous NO biosynthesis pathways.

Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer

“…In addition, the clinical application of iNOS inhibitors for cancer therapy is controversial. Some studies have reported that the low level of iNOS is associated with a poor prognosis in CRC patients [160]; however, other studies have indicated a correlation between the low survival rates of patients and high level of iNOS in tumor tissues [54,161]. One study has even demonstrated that iNOS expression in tumors does not always correspond to the NO production level [162].…”

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

“…Once macrophages are recruited in the tumors, hypoxia-dependent transcription factors HIF1/2α reprograms macrophages into pro-tumoral phenotype that expresses IL-6, VEGF, and inducible nitric oxide synthase (iNOS) and arginase to promote tumor growth, angiogenesis, and immunosuppression ( 124 , 125 ). While iNOS is typically induced by M1 macrophages, studies have found that M2-like TAMs express iNOS at lower levels than M1 macrophages and these low levels of NO produced by TAMs inhibits tumor cell apoptosis and serves a cytoprotective function ( 126 – 128 ). Recent studies have shown that PTEN/PI3K/AKT signaling axis and Syk-Rac2 signaling axis promotes the stabilization of HIF1/2α in TAMs and polarization of macrophages into immunosuppressive phenotype in solid tumors ( 129 – 132 ).…”

Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion

“…There is considerable evidence demonstrating a dual role of NO and S-nitrosylation in cancer risk and metastasis (Burke et al, 2017;Rizza and Filomeni, 2018;Ehrenfeld et al, 2019;Hays and Bonavida, 2019;Holotiuk et al, 2019;Somasundaram et al, 2019). The available evidence demonstrates a positive correlation between NO biosynthesis, tumor development and degree of malignancy in a variety of cancers (breast, pancreatic, liver, cervical, ovary, melanoma, nasopharyngeal, stomach, colon, lung, oral, esophagus, glioma, and prostate cancer) (Monteiro et al, 2015;Vanini et al, 2015;Burke et al, 2017;Thomas and Wink, 2017;Somasundaram et al, 2019).…”

“…On the other hand, when the endothelium is stimulated with pro-inflammatory agonist, the effects of NO have not been completely consistent. There is a vast body of evidence showing an inhibitory effect of NO on stimulated leukocyte adhesion (De Caterina et al, 1995;Liu et al, 1998;Baatz and Pleyer, 2001;Lelamali et al, 2001;Lo et al, 2001;Jiang et al, 2005;Shelton et al, 2008); while other reports demonstrate either no effect of inhibition of NO on leukocyte adhesion (Hickey et al, 2001;Shelton et al, 2008) or promotion -mediated by NO -of leukocyte adhesion in response to challenge with cytokines (Bessa et al, 2002;Joussen et al, 2002). These discrepancies may be due to several differences in experimental approaches including timing and duration of the application of agonist/antagonist.…”