Nitrosative Stress as a Mediator of Apoptosis: Implications for Cancer Therapy

Nitric oxide (NO center dot) is now recognised as one of the most important molecules influencing the development, progression and treatment of cancer. A key component of its action is as a negative and positive regulator of apoptosis. Broadly, constitutive levels of NO center dot (nM), are capable of inhibiting numerous signalling pathways in both normal and cancer cells. These include soluble guanylate cyclase, leading to reduced Ca++ signalling, inhibition of caspases and scavenging of reactive oxygen species, all of which promote survival signalling. High concentrations (mu M-mM) on the other hand, generally promote apoptosis. Pathways involving cGMP, cytochrome c release, mitogen activated kinases, ceramide and poly(ADP) ribose polymerase have all been implicated. The role of p53 in NO center dot-induced cell death has been widely studied. In many cell types p53-dependent signalling is involved, while in others, apoptosis occurs in the absence of functional p53. There is also evidence that the tumour microenvironment, where low oxygen and glucose levels prevail, enhances cell death signalling by NO center dot and peroxynitrite, thus tumours may be more sensitive to high levels of NO center dot than their normal tissue counterpart. The cytotoxicity of NO center dot has been studied directly in many tumour models, both in vitro and in vivo. In all cases, high concentrations of NO center dot, generated by donor drugs or by iNOS gene transfer caused extensive tumour cell death, which was enhanced by the ability of NO center dot to diffuse readily from its source of generation to most cells within tumours. NO center dot was also a very effective enhancer of conventional chemo-and radiotherapy. Thus, NO center dot therapy has great potential to improve the treatment of cancer.