Molecular targets of nitric-oxide-donating aspirin in cancer

Nitric-oxide-donating aspirin (NO-ASA), consisting of ASA (aspirin) plus an -ONO₂ moiety linked to it via a molecular spacer, is a new drug for cancer prevention. NO-ASA seems to overcome the low potency and toxicity of traditional ASA. The -ONO₂ moiety is responsible for releasing NO, and it appears to be required for biological activity. In studies in vitro, NO-ASA inhibits the growth of colon, pancreatic, prostate, lung, skin, leukaemia and breast cancer cells, and is up to 6000-fold more potent than traditional ASA. This effect is owing to cell kinetics [inhibition of proliferation, induction of apoptosis (multiple criteria) and blocking the G₁ to S cell-cycle transition] and cell signalling [inhibition of Wnt signalling (IC₅₀ = 0.2 μM), inhibition of NF-κB (nuclear factor κB) activation (IC₅₀ = 7.5 μM), inhibition of nitric oxide synthase-2 expression (IC₅₀ = 48 μM), inhibition of MAPK (mitogen-activated protein kinase) signalling (IC₅₀ = 10 μM) and induction of cyclooxygenase-2 at approx. 10 μM]. In studies in vivo, NO-ASA inhibits intestinal carcinogenesis in Min mice (tumour multiplicity was reduced by 59% after 3 weeks, with no effect in control animals and no side effects) and in the N-nitrosobis(2-oxopropyl)amine model of pancreatic cancer, where there was an 89% reduction in NO-ASA (3000 p.p.m. in the diet)-treated animals (P < 0.001). There was no statistically significant effect by traditional ASA at equimolar doses. Our data indicate that NO-ASA is a highly promising agent for the prevention and/or treatment of cancer.