David A. Wink

Chapter 3 – The Chemical Biology of Nitric Oxide

Publisher Summary The multiple effects of nitric oxide (NO) in biological systems have resulted in intense investigation into the mechanisms of NO-mediated events. The chemistry of NO is the primary determinant of its biological properties. However, not all the reactions of NO that can be performed in test tube are pertinent in vivo. This chapter provides a guide through the diverse reactions of NO in biological systems. The scheme of the chemical biology of NO divides the reactions into the two categories of direct and indirect effects. Direct effects are defined as those reactions that are fast enough to occur between NO and specific biological targets. Indirect effects do not involve NO, but rather, are mediated by reactive NO species formed from the reaction of NO with either oxygen or superoxide. These species can mediate either nitrosative or oxidative stress. Aspects of the chemical biology of NO relating to biological molecules such as guanylate cyclase, cytochrome P-450, nitric oxide synthase, catalase, and DNA are reviewed and the possible roles NO performs in different biological situations are explored.

Advances in Breast Cancer Therapy Using Nitric Oxide and Nitroxyl Donor Agents

Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory findings regarding its role in cancer biology. With greater understanding, it is now well established that the biphasic effects of NO are concentration dependent. Low flux of NO less than 10 nM is essential for normal physiological functions such as vascular maintenance. Intermediate levels of NO higher than 100 nM affect critical pathways that lead to tumor progression, whereas higher flux NO (>800 nM) induces tumor regression. Nitric oxide synthase (NOS) enzymes, particularly inducible NOS (iNOS), have often been shown to exert both pro- and antitumor effects. The elucidation of the involvement of intermediate NO flux generated by iNOS during cancer progression has led to the rapid development of several classes of NOS inhibitors with potent therapeutic effects. In contrast, the generation of higher NO flux in the tumor microenvironment tips the balance to favor cytostasis and cell killing. Toward this end, several classes of NO donors (e.g., nitrate esters, S-nitrosothiols, and diazeniumdiolates) have been examined both in vitro and in vivo and have demonstrated vast potential as chemotherapeutic agents as well. Recently, nitroxyl (HNO) has emerged as a key player with promising therapeutic potential as it exhibits properties that are often orthogonal to NO. Significant potential of HNO in the treatment of cardiovascular disease, clinical usage as an alcohol deterrent agent, and chemotherapeutic activity are only a few of its properties that have recently been explored. In this chapter, we briefly review some of the key pathways/chemical modifications by which NO and HNO exert their physiological outcome in cancer biology. NOS inhibition and utilization of NO donors as effective therapeutic options for NO-based therapy, HNO donors and their utilization as chemo drugs, and lastly NO/HNO-based hybrid drugs are discussed to show the therapeutic depth and potential for NO and HNO in cancer treatment.

Determinants of Nitric Oxide Chemistry

Publisher Summary Nitric oxide (NO) has emerged as one of the most diverse and important ubiquitous biological mediators. It plays a functional role in processes ranging from neurological function and vascular tonicity to pathogen eradication. It is a signaling mediator with diverse as well as opposing biological activities. The complexity of the NO response reflects the variety of its chemical reactions and biological properties. Steady-state NO concentration is a key determinant of its biological outcome as precise cellular responses are differentially regulated by specific NO concentrations. In general, lower NO concentrations promote cell survival and proliferation, while higher levels favor cell cycle arrest, apoptosis, and/or senescence. Free radical interactions also influence NO signaling by reducing NO bioavailability. Reactive nitrogen species generated during these processes also have biological effects by increasing oxidative and nitrosative stress responses. Moreover, a number of factors influence NO formation and concentration, including diffusion, consumption, and substrate availability, which are referred to as kinetic determinants for molecular target interactions. Kinetic determinants are the chemical and biochemical parameters that shape cellular responses to NO. This chapter discusses these chemical interactions and their influence on NO signaling and cellular response. It also discusses the involvement of kinetic determinants as they relate to the direct and indirect effects of NO responses during normal physiology and disease processes. Rates of NO formation, diffusion and consumption, radical/target interactions, and O 2 concentration all contribute to cellular and tissue-specific responses to NO. NO concentration drives its chemistry (direct vs indirect effects), diffusion distance, and the specific targets that it interacts with.