Nitrosative stress in cancer therapy

Reactive nitrogen species play important roles in cell signalling, but when present at high concentrations they can subject cells to nitrosative stress, which may lead to cell death. Nitric oxide (NOx) is now recognized as playing important roles in cancer aetiology and progression and it can influence the outcome of cancer treatment. It is synthesised by the action of nitric oxide synthases (NOSs) on the amino acid arginine. Although NOx is not highly reactive with biological molecules, it reacts readily with other oxygen radicals to generate highly damaging reactive nitrogen species such as peroxynitrite, nitrogen dioxide and dinitrogen trioxide. These are potent inducers of apoptosis and necrosis. They may also inhibit DNA repair mechanisms, leading to mutation and carcinogenesis. Both inhibition and over-production of NOx have been investigated as strategies for cancer therapy. There is clear evidence that administration of competitive inhibitors of NOS can significantly slow the growth of solid tumors in rodent models, probably by reducing blood flow, and this creates a hypoxic environment that is conducive to the activation of bioreductive anticancer agents. Alternatively, generation of NOx concentrations in the high micromolar range by NOx donor drugs or gene therapy with inducible NOS is directly cytotoxic to cells and has been shown to inhibit tumor growth. At these high concentrations NOx is also an excellent sensitizer to radiation and to some chemotherapeutic agents, particularly cisplatin. Thus, manipulation of NOx levels in tumors offers exciting opportunities to improve the effectiveness of cancer treatment.