In comparison to the oxygen radicals, NO is a more stable oxidant, easily crosses lipid bilayers, and generates several types of posttranslational modifications with known ability to alter protein function and stability; these modifications are dependent on both NO concentration and temporal availability, resulting in a dynamic and reversible situation12
January 14, 2022
In comparison to the oxygen radicals, NO is a more stable oxidant, easily crosses lipid bilayers, and generates several types of posttranslational modifications with known ability to alter protein function and stability; these modifications are dependent on both NO concentration and temporal availability, resulting in a dynamic and reversible situation12. numerous anti-oxidant agents are clinically available, and we further propose that the pharmacological attenuation of these GSK163090 inflammatory processes, particularly the reactive nitrogen species, will restore the cancer cells to an apoptosis-permissive and growth inhibitory state. Our mouse model data using an arginine antagonist that prevents enzymatic production of nitric oxide, directly supports this view. We contend that selected antioxidants be considered as part of the cancer treatment approach, as they are likely to provide a novel and mechanistically justified addition for therapeutic benefit. Background The most commonly recognized features of cancer-associated inflammation are those also expressed by the innate immune system, normally activated in response to stress or infection and which function teleologically Rabbit Polyclonal to FER (phospho-Tyr402) during the initiation of wound control 1. The observed chronic inflammatory milieu in notable subsets of human cancers, and particularly in GSK163090 melanoma, is proposed to support tumor growth, plasticity, and resistance to therapy 2,3,4,5,6. Unfortunately, dysregulated persistent inflammation contributes to the chronic phase of many diseases, including maintenance of many cancers. It is accepted that inflammation drives development of some cancers which adapt to thrive in the oxidant-rich microenvironment as described initially in the review by Coussens and Werb5, by co-opting expression of inflammatory mediators 7. From our view, this continues to provide a persistent and self-perpetuating oxidative stress composed of both Reactive Nitrogen Species (RNS) and Reactive Oxygen Species (ROS), and derived from pro-inflammatory interleukins, chemokines, NOSs (nitric oxide synthases) often via growth factor receptors4. The critical oxidant sources are now realized to be more than reactive oxygen molecules, as the chronic production of another oxidant, NO (nitric oxide), also plays a major role in oxidative stress in melanoma and other cancers 4,8, 9, 10,11 and the aberrant constitutive RNS is argued here as possibly a more important source of oxidative stress in many cancers. In comparison to the oxygen radicals, NO is a more stable oxidant, easily crosses lipid bilayers, and generates several types of posttranslational modifications with known ability to alter protein function and stability; these modifications are GSK163090 dependent on both NO concentration and temporal availability, resulting in a dynamic and reversible situation12. A mathematical model of cutaneous melanoma predicted sufficient concentrations of NO at the periphery of a tumor to stimulate cell proliferation, lymphangiogenesis, and inhibit apoptosis 13. Inflammation driven NO supports melanoma growth, and apoptosis resistance In melanocytes, the precursor cell of melanoma, the pigment eumelanin provides a redox function supporting an antioxidant intracellular environment; however in melanoma, a pro-oxidant status develops8. The enzymatic production of NO is cell type specific with cytokine-driven inducible NOS (iNOS) noted initially GSK163090 for the burst of higher levels as part of the pathogen defense system. Neuronal cells use nNOS (to produce NO for signaling, and as melanocytes are of neuroectoderm origin, it is not surprising to find nNOS also expressed. The third NOS, endothelial NOS, regulates NO production in endothelia and is responsible for vascular relaxation, and has also been reported to be expressed in melanoma 14. In melanoma tumors, we 9, 10, 4,11 and others 6,8 document expression of NOS, particularly in the melanoma tumor cytoplasm of ~60% of advanced patients, and provided independent prognostic value by predicting decreased survival, so that the hazard ratio of iNOS positive patients was 4.6 by multivariate analysis9. This was an unexpected finding as the anti-iNOS antibody was employed to identify activated macrophages, which were also often positive, but for which the positivity did not prove prognostic. Further evidence supporting intracellular NO production was by use of DAF-2DA staining 4 as well as identification of irreversible protein nitration and the reversible thiol modifications known as S-NO (S-nitrosylation) 4, 9, 10, 11. Using a human cell line model, experiments were performed to scavenge endogenous NO which resulted in melanoma cell growth inhibition; the growth was restored with an RNS.