Apoptosis‐Inducing High ^.NO Concentrations Are Not Sustained Either in Nascent or in Developed Cancers

Abstract

Nitric oxide ((.)NO) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high (.)NO concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-beta1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient (.)NO levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low (.)NO levels are caused by inhibition of iNOS by N-chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl- to HOCl, which N-chlorinates taurine at its concentration of 19 mM in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low (.)NO concentrations arise from the inhibition of iNOS by N-bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br- to HOBr, which N-brominates taurine to N-bromotaurine at its concentration of 15 mM in eosinophils. In microvascularized tumors, the (.)NO concentration is further depleted; (.)NO is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin, and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O2 or nutrient supply. They actually decrease the loss of (.)NO to RBCs.

Production of Nitric Oxide and Expression of Inducible Nitric Oxide Synthase in Ovarian Cystic Tumors

“…High levels of NO have also been shown to induce apoptosis. Correspondingly, high concentrations of NO have not been found to be maintained in many malignant neoplasias [38]. These opposing actions of NO have been attributed to factors such as differences in the isoform of NOS expressed, the level of NOS expression, and the type of cell involved in either in vitro or in vivo systems [39].…”

Oxidative Stress and HPV Carcinogenesis

“…At high concentration, i.e. above 10 −6 M, a concentration easily attained during the macrophage/neutrophils activation, •NO induces apoptosis by nitrosating thiol groups of cellular proteins and enzymes [75]. Conversely, •NO concentrations around 2 × 10 −8 M are essentially mutagenic [76] and induce the release of vascular endothelial growth factor (VEGF) [77,78].…”

“…Conversely, •NO concentrations around 2 × 10 −8 M are essentially mutagenic [76] and induce the release of vascular endothelial growth factor (VEGF) [77,78]. Thus, even though initially considered a potential mechanism of neoplastic growth control, it is now evident that •NO fails to attain apoptosis-inducting concentration in the vast majority of cancers of any histological origin [75]. In the case of cervical carcinomas and HPV-positive dysplastic lesions, the reason for the inadequate level of •NO is the insufficient expression of iNOS that appears to be progressively reduced with the histological severity of lesions [79,80].…”

NO to Breast: When, Why and Why Not?

“…In some tissues, iNOS mRNA expression is not associated with iNOS enzyme and NO production [142]. The variations in the effect of iNOS in breast tumors could be explained due to the inability of various biological systems and especially tumor microenvironments to sustain high NO concentrations [143]. Failure to produce sufficiently high NO concentration could be partially attributed to transcriptional inhibition of iNOS expression by TGF-β 1, which is over expressed in breast cancer [144].…”