The mechanism of action of nitric oxide-donating aspirin.
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.
Kashfi
Khosrow
K
Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031, USA. Kashfi@med.cuny.edu
Rigas
Basil
B
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D001241:Aspirin