Nitric oxide and cancer: a review

World Journal of Surgical Oncology Nitric oxide and cancer: a review Sheetal Korde Choudhari 0 Minal Chaudhary 2 Sachin Bagde 1 Amol R Gadbail 2 Vaishali Joshi 0 0 Department of Oral Pathology & Microbiology, Yerala Dental College and Hospital , Institutional Area, Sector 4, Kharghar, Navi Mumbai, Maharashtra 410 210 , India 1 Department of Oral Surgery, Yerala Dental College and Hospital , Institutional Area, Sector 4, Kharghar, Mumbai, Maharashtra 410 210 , India 2 Department of Oral Pathology & Microbiology, Sharad Pawar Dental College , DMIMS, Sawangi(M), Wardha, Maharashatra 442 004 , India Nitric oxide (NO), is a ubiquitous, water soluble, free radical gas, which plays key role in various physiological as well as pathological processes. Over past decades, NO has emerged as a molecule of interest in carcinogenesis and tumor growth progression. However, there is considerable controversy and confusion in understanding its role in cancer biology. It is said to have both tumoricidal as well as tumor promoting effects which depend on its timing, location, and concentration. NO has been suggested to modulate different cancer-related events including angiogenesis, apoptosis, cell cycle, invasion, and metastasis. On the other hand, it is also emerging as a potential anti-oncogenic agent. Strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain are being investigated. However, further validation and experimental/clinical trials are required for development of novel strategies based on NO for cancer treatment and prevention. This review discusses the range of actions of NO in cancer by performing an online MEDLINE search using relevant search terms and a review of the literature. Various mechanisms by which NO acts in different cancers such as breast, cervical, gastric,colorectal, and head and neck cancers are addressed. It also offers an insight into the dichotomous nature of NO and discusses its novel therapeutic applications for cancer prevention and treatment. Breast cancer; Gastric cancer; Lung cancer; Head and Neck cancer; H; Pylori; Human papillomavirus; Nitric oxide; Nitric oxide synthase - Review Introduction Nitric oxide (NO) is a short-lived, endogenously produced gas that acts as a signaling molecule in the body. Ignarro et al. and Palmer et al. simultaneously identified NO as the endothelium-derived relaxing factor in 1987 [1,2]. It is synthesized by nitric oxide synthase (NOS) enzymes; produced by mammalian cells at an appropriate magnitude and tempo, it serves as a key signaling molecule in various physiological processes. On the other hand, excessive and unregulated NO synthesis has been implicated as causal or contributing to pathophysiological conditions including cancer. Expression of NOS has been detected in various cancers such as cervical, breast, central nervous system, laryngeal, and head and neck cancers [3-7]. NO has been suggested to modulate different cancer-related events [8]. However, several lines of research have indicated that NO may have dual effects in cancer. At concentrations measurable in many different types of clinical samples, NO seems to promote tumor growth and proliferation. In contrast to this, NO is said to have tumoricidal effects;various direct and indirect mechanisms have been proposed for its antitumor properties [9,10], although there is lack of data directly on cancer patients. Nevertheless, the tumoricidal properties of NO are being investigated for therapeutic purposes. NO is used alone or in combination with other cytotoxic agents. In order to obtain a better insight into the dichotomous nature of NO, an online search using proper search terms through MEDLINE was undertaken and the relevant literature was reviewed. This review discusses the diverse actions of NO in cancer and NOs novel applications in cancer treatment and prevention. Biological and physiological aspects of NO NO, a short-lived endogenously produced gas, is synthesized by a complex family of NOS enzymes. Mammalian cells are endowed with three genes encoding distinct isoforms of NOS NOS1, NOS2, and NOS3 with 5157% homology between isoforms and different localizations, regulation, catalytic properties, and inhibitor sensitivity. NOS1, also known as nNOS (isoform first purified and cloned from neuronal tissue), and NOS3 or eNOS (isoform first found in endothelial cells) are also termed as constitutive since they are expressed continuously in neurons and endothelial cells, respectively. They are also dependent on a rise in tissue calcium concentration for activity and therefore produce low, transient concentrations of NO. In contrast, NOS2 is an inducible, calcium-independent isoform, also called iNOS. Unlike NOS1 and NOS3, induction of NOS2 results in continuous production of NO [11]. It is inducible by immunological stimuli in virtually all nucleated mammalian cells. Once induced, the enzyme continues to produce much higher NO concentrations for many hours or even days. An important regulator of NOS2 is the tumor suppressor gene p53 which senses raised cellular NO and inhibits NOS2 by a negative feedback loop [12]. This relationship has important implications in cancer. Contrary to conventional biosignaling molecules that act by binding to specific receptor molecules, NO manifests its biological actions via a wide range of chemical reactions. The precise reactions depend on the concentration of NO achieved and on subtle variations in the composition of intra- and extracellular milieu [11]. Under normal physiological conditions, cells produce small but significant amounts of NO which contribute to regulation of anti-inflammatory effects and its antioxidant properties [13,14]. However, in tissues with a high-output of NO, iNOSisupregulated and effects such as nitration (addition of NO2), nitrosation (addition of NO+), and oxidation will prevail [13]. Interaction of NO with O2 or O2- results in formation of reactive nitrogen species (RNS). The RNS, dinitrogen trioxide (N2O3) and peroxynitrite (ONOO), can induce two types of chemical stresses,nitrosative and oxidative [15]. N2O3 is a potent nitrosating agent which has been shown to N- and S- nitrosate a variety of biological targets to yield potentially carcinogenic nitrosamines and nitrosothiol derivatives. N-nitrosation may have important implications in the known association between chronic inflammation and malignant transformation [15,16]. O2- and NO may rapidly interact to produce the potent cytotoxic oxidants peroxynitrite (ONOO-) and its conjugate acid ONOOH. Peroxynitrite in natural solution is a powerful oxidant, oxidizing thiols or thioethers, nitrating tyrosine residues, nitrating and oxidizing guanosine, degrading carbohydrates, initiating lipid peroxidation and cleaving DNA, which has important implications in cancer [17,18]. Diverse actions of NO in cancer NO has been reported to exert dichotomous effects within the multistage model of ca (...truncated)