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 microM), inhibition of NF-kappaB (nuclear factor kappaB) activation (IC50=7.5 microM), inhibition of nitric oxide synthase-2 expression (IC50=48 microM), inhibition of MAPK (mitogen-activated protein kinase) signalling (IC50=10 microM) and induction of cyclo-oxygenase-2 at approx. 10 microM]. 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.
Kashfi
K
K
Department of Physiology and Pharmacology, City University of New York Medical School, NY 10031, USA. kashfi@med.cuny.edu
Rigas
B
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000517:prevention & control; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000517:prevention & control*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D020030:Nitric Oxide Donors; D001241:Aspirin