Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: implications for chemoprevention.
Nitric oxide (NO)-releasing aspirin (ASA), consisting of a traditional ASA molecule to which a NO-donating moiety is covalently bound, is a promising colon cancer chemopreventive agent. NO-ASA inhibits colon cancer cell growth more potently than ASA by inhibiting cell proliferation and enhancing cell killing. We examined in cultured human colon cancer cells the effect of NO-ASA on the beta-catenin/T-cell factor signaling pathway, nuclear factor-kappaB, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the beta-catenin/T-cell factor signaling pathway (IC(50), 1.1 microM), nuclear factor-kappaB DNA binding (IC(50), 7.5 microM), and NO synthase 2 expression (IC(50), 2 microM). Interestingly, NO-ASA induced COX-2 expression, although it had no effect on COX-1. COX-2 induction was accompanied by increased prostaglandin E(2) production. These effects occurred at NO-ASA concentrations below or near its IC(50) for cell growth (IC(50), 2-50 microM). The metabolism of NO-ASA by these cells is characterized by a rapid deacetylation step and the formation of a conjugate with glutathione. NO-ASA had no effect on intracellular cyclic GMP concentrations. We propose a model incorporating the pleiotropic effects of NO-ASA on cell signaling and postulate that collectively these effects may contribute to its strong chemopreventive effect.
Williams
Jennie L
JL
American Health Foundation Cancer Center, Institute for Cancer Prevention, 1 Dana Road, Valhalla, NY 10595, USA.
Nath
Niharika
N
Chen
Jie
J
Hundley
Thomas R
TR
Gao
Jianjun
J
Kopelovich
Levy
L
Kashfi
Khosrow
K
Rigas
Basil
B
D001241:Aspirin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006152:Cyclic GMP / Q000378:metabolism; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004273:DNA, Neoplasm / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C098312:nitroxy-butyl-acetylsalicylic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D006152:Cyclic GMP; D001241:Aspirin