The mechanism of action of nitric oxide-donating aspirin

Biochem Biophys Res Commun. 2007 Jul 13;358(4):1096-101. doi: 10.1016/j.bbrc.2007.05.038. Epub 2007 May 15.


NO-donating aspirin (NO-ASA) is a promising anticancer drug. We studied the contribution of NO-ASA's components (ASA, NO-releasing moiety, and spacer linking them) to its effect. The ASA and NO-releasing moieties play no biological role: ASA inhibits the growth of colon cancer cells >100-fold less potently that NO-ASA; and denitrated NO-ASA plus the NO-donor SNAP releasing the same amount of NO as NO-ASA, inhibit the growth of cancer cells >50-fold less potently than NO-ASA. The biologically active moiety of NO-ASA is the spacer: it is chemically reactive (studies with NO-ASA radiolabeled at the spacer demonstrated that it binds to proteins); and compounds in which the ASA or the NO-releasing groups are replaced inhibit cell growth similar to NO-ASA. We propose a mechanism of action of NO-ASA involving formation of quinone methide from its para and ortho isomers and of a carbocation from the meta, with the NO-releasing group functioning as a leaving group.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Antineoplastic Agents / administration & dosage*
  • Aspirin / administration & dosage*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • HT29 Cells
  • Humans
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / administration & dosage*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Nitric Oxide Donors
  • Nitric Oxide
  • Aspirin