Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies

The diatomic radical nitric oxide (NO) has been the cause of intense debate with implication in carcinogenesis, tumour progression, invasion, angiogenesis and modulation of therapeutic responses. The tumour biology of NO is highly complex, and this review summarises the various protective and damaging mode of action of NO. We reviewed all published literature addressing the complexities of the role of NO in the altered biology of cancer and evaluating promising therapeutic roles of NO/iNOS for anti-cancer therapy. The available experimental evidences highlight contrasting pro- and anti-tumour effects of iNOS expression, which appear to be reconciled by consideration of the concentrations of NO involved, the temporo-spatial mode of NO action, intracellular targets, cellular redox state and the timing of an apoptotic stimulus. Several clinical and experimental studies indicate that the presence of NO in tumour microenvironment is detrimental to tumour cell survival and metastasis. In contrast, numerous reports suggest that NO can have tumour-promoting effects. NO is a 'double-edged sword' in cancer, and this review offers insight into the dichotomous nature of NO and discuss the therapeutic gain that can be achieved by manipulating tumour NO. NO may exert a biphasic response, such that when NO levels go beyond a critical concentration that would be suitable for tumour growth and survival, growth arrest and/or apoptotic pathways are initiated. These characteristics of NO have been exploited therapeutically with impressive effects in pre-clinical models of cancer to slow tumour growth and to enhance the efficacy of both chemotherapy and radiotherapy.