It is now generally agreed that NO has a highly context-dependent dose–response stimulation-inhibition relationship with cytotoxicity at high doses and mitogenicity at low doses [22]. Thus, NO has the ability to both

promote and suppress cancer. However, these binary either/or descriptions are an oversimplification. At low constitutive levels induced by hypoxia in tumors, NO levels are optimal for the mediation of aberrant, proliferative signaling. In contrast, levels either above or below this optimal range can have the opposite effect and activate signal transduction pathways that contribute to/result in growth inhibition or cell death. NO is a radical with a free electron capable click here of interacting with reactive oxygen species (ROS) such as the superoxide anion to form a variety of highly reactive

nitrogen oxides (NOx). The term nitrosative stress refers to the formation of NOx compounds such as peroxynitrite (ONOO−), nitrogen dioxide (NO2), and dinitrogen trioxide (N2O3) that are responsible for cytotoxic nitration and oxidation reactions  [23] leading to apoptosis and cell death. In particular, the formation of peroxynitrite is a first-order reaction  [23] dependent on the concentrations of NO and the superoxide anion and, therefore, on oxygen tension, because in the presence of hypoxia, both NO and ROS such as the superoxide anion will be less prevalent. Xie et al [24] demonstrated that transfection of murine K-1735 melanoma cells with inducible NOS leading to the generation of high levels of NO resulted in suppression

of tumorigenicity and metastasis. The cytotoxicity of CYC202 cell line higher concentrations of NO is consistent with the assumption that the toxic effect becomes apparent above a threshold dose of NOx. This balance between mitogenic and toxic effects of NO in tumor cells is potentially attributable to an increased susceptibility to free radical damage due to severe impairment of the antioxidant defense system [25] compared with healthy cells. In cancer cells, reactive oxygen/nitrogen species “reprogram” the cellular metabolism toward a dependence on glucose use, termed the Warburg effect, a signature of virtually all tumors and the basis of fluorodeoxyglucose positron emission tomography imaging, to support anabolic proliferation. The fact that this core feature of tumors, metabolic reprogramming, Rho is dependent on redox signaling implies that ROS/reactive nitrogen species (RNS) levels are higher in tumors than in healthy tissue, resulting in a differential sensitivity to oxidant stress [26]. Indeed, the presence of high levels of ROS in tumors has been linked with cell cycle arrest and apoptosis [27]. However, NOx cytotoxicity may not require superelevated doses but rather approximate “normalization” to physiological levels [27], because shifts in a particular direction can have important consequences. For example, Frederiksen et al.