Molecular Pathways: Inflammation-Associated Nitric-Oxide Production as a Cancer-Supporting Redox Mechanism and a Potential Therapeutic Target

• Published in: Clinical cancer research Vol. 19; no. 20; pp. 5557 - 5563
• Main Authors: GRIMM, Elizabeth A, SIKORA, Andrew G, EKMEKCIOGLU, Suhendan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2013
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Humans; Inflammation - metabolism; Medical sciences; Melanoma - metabolism; Melanoma - pathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Nitric Oxide - biosynthesis; Oxidation-Reduction; Pharmacology. Drug treatments; Signal Transduction - drug effects; Translational Medical Research; Tumor Microenvironment - immunology; Tumors; Treatment; Targeting; Targeted therapy; Nitric oxide; Biosynthesis; Inflammation; Malignant tumor; Mechanism of action; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-1554

It is widely accepted that many cancers express features of inflammation, driven by both microenvironmental cells and factors, and the intrinsic production of inflammation-associated mediators from malignant cells themselves. Inflammation results in intracellular oxidative stress with the ultimate biochemical oxidants composed of reactive nitrogens and oxygens. Although the role of inflammation in carcinogensis is well accepted, we now present data showing that inflammatory processes are also active in the maintenance phase of many aggressive forms of cancer. The oxidative stress of inflammation is proposed to drive a continuous process of DNA adducts and crosslinks, as well as posttranslational modifications to lipids and proteins that we argue support growth and survival. In this perspective, we introduce data on the emerging science of inflammation-driven posttranslational modifications on proteins responsible for driving growth, angiogenesis, immunosuppression, and inhibition of apoptosis. Examples include data from human melanoma, breast, head and neck, lung, and colon cancers. Fortunately, numerous antioxidant agents are clinically available, and we further propose that the pharmacologic attenuation of these 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.