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Molecular targets of nitric-oxide-donating aspirin in cancer.

Abstract
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.
AuthorsK Kashfi, B Rigas
JournalBiochemical Society transactions (Biochem Soc Trans) Vol. 33 Issue Pt 4 Pg. 701-4 (Aug 2005) ISSN: 0300-5127 [Print] England
PMID16042578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Nitric Oxide Donors
  • Aspirin
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
  • Anticarcinogenic Agents (pharmacology)
  • Aspirin (pharmacology)
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • Colonic Neoplasms (prevention & control)
  • Humans
  • Mice
  • Neoplasms (prevention & control)
  • Nitric Oxide Donors (pharmacology)
  • Pancreatic Neoplasms (pathology)

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