The diatomic radical
nitric oxide has been the focus of numerous studies involved with every facet of
cancer. It has been implicated in
carcinogenesis, progression, invasion,
metastasis, angiogenesis, escape from immune surveillance, and modulation of therapeutic response. In recent years, an increasing number of studies have suggested the possible involvement of
nitric oxide in multiple
cancer types, including
melanoma. It is perhaps not surprising that conflicting viewpoints have arisen as to whether
nitric oxide is beneficial or deleterious in
cancer. However, it has become clear that
nitric oxide possesses modulatory properties in a number of signal transduction pathways that depend on concentration and context. Our laboratory has shown that
tumor expression of
inducible nitric oxide synthase in
melanoma patients results in poor survival. Furthermore, we demonstrated that the removal of endogenous
nitric oxide in
melanoma cell lines led to increased sensitivity to
cisplatin-induced apoptosis in a p53-dependent manner. Others have shown anti-apoptotic properties of NO in
melanoma cells. However, several studies also suggest that NO can inhibit
metastasis and diminish resistance. Despite the apparently conflicting observations, it is evident that NO is involved in
melanoma pathology. The purpose of this review is to summarize the current literature relating to the role of NO in
cancer with particular emphasis on its relevance to therapeutic resistance in
melanoma. Recent evidence suggests the involvement of an intricate and complex interplay between
reactive nitrogen species and
reactive oxygen species. The importance of
nitric oxide and its balance with other oxidative agents in the regulation of
cancer cell response to
therapies will be discussed. This balance may serve as an important focal point in determining patient response to
therapy. The ability to control this balance could significantly influence outcome.