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NO-donating aspirin inhibits both the expression and catalytic activity of inducible nitric oxide synthase in HT-29 human colon cancer cells.

Abstract
Nitric oxide-releasing aspirin (NO-ASA) is emerging as a potentially important chemopreventive agent against colon cancer. We examined in HT-29 human colon adenocarcinoma cells the effect of NO-ASA on the inducible form of nitric oxide synthase (NOS2), an enzyme implicated in colon carcinogenesis. NO-ASA inhibited in a time- and concentration-dependent manner the expression of NOS2 up to 70% compared to control (IC50 for this effect = 46 microM). NO-ASA also decreased the corresponding steady-state mRNA levels and this reduction preceded the reduction of protein levels by at least 6 h. NO-ASA also reduced the enzymatic activity of NOS2, as determined by a direct enzyme assay (maximal reduction = 80%) and by determining the accumulation of NO in the culture medium (IC50 for this effect = 36 microM). These effects of NO-ASA on NOS2 were paralleled by inhibition in cell growth (IC50 = 8.5 microM). These findings indicate that NO-ASA profoundly inhibits both the expression and enzymatic activity of NOS2 and suggest that these effects may represent an important mechanism for the colon cancer chemopreventive effect of NO-ASA.
AuthorsAdam Spiegel, Thomas R Hundley, Jie Chen, Jianjun Gao, Nengtai Ouyang, Xiaoping Liu, Mae F Go, George J Tsioulias, Khosrow Kashfi, Basil Rigas
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 70 Issue 7 Pg. 993-1000 (Oct 01 2005) ISSN: 0006-2952 [Print] England
PMID16105666 (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.)
Chemical References
  • DNA Primers
  • Nitric Oxide Donors
  • RNA, Messenger
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Aspirin
Topics
  • Adenocarcinoma (enzymology, pathology)
  • Aspirin (pharmacology)
  • Base Sequence
  • Catalysis
  • Colonic Neoplasms (enzymology, pathology)
  • DNA Primers
  • HT29 Cells
  • Humans
  • Nitric Oxide Donors (pharmacology)
  • Nitric Oxide Synthase (antagonists & inhibitors, genetics, metabolism)
  • Nitric Oxide Synthase Type II
  • RNA, Messenger (genetics)

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