title: Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: in vitro evidence querying the NO donor functionality.
abstract: Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than one hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural "linker" as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, USA.
authors.forename: Tareisha
authors.initials: T
authors.lastname: Dunlap
authors.forename: Samer O
authors.initials: SO
authors.lastname: Abdul-Hay
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Ghenet K
authors.initials: GK
authors.lastname: Hagos
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sinha
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Huali
authors.initials: H
authors.lastname: Wang
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D006801:Humans; D008264:Macrophages; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D009574:Nitro Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C498045:NCX 4040; D009566:Nitrates; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; C098312:nitroxy-butyl-acetylsalicylic acid; D009569:Nitric Oxide; D001241:Aspirin