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Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model.

Abstract
To evaluate the chemopreventive effect of nitric oxide-donating aspirin (NO-ASA), an ASA bearing a NO-releasing moiety, against pancreatic cancer, we studied six groups of female Syrian golden hamsters: groups 1 to 3 (n = 12 each) were given saline and groups 4 to 6 (n = 17) the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in five weekly injections (the first, 70 mg/kg, and the remaining, 20 mg/kg each). Control and BOP-treated hamsters were fed a NO-ASA 3,000 ppm or conventional ASA 3,000 ppm or control diet for 19 weeks. Groups 1 to 3 had no tumors. Compared with the BOP/vehicle group, NO-ASA reduced the incidence (88.9%, P < 0.003) and multiplicity (94%, P < 0.05) of pancreatic cancer; ASA had no statistically significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma. The proliferation (proliferating cell nuclear antigen) / apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling) ratio of ductal cells increased with the histologic severity of the ductal lesion; NO-ASA suppressed it significantly during all stages except PanIN1A. p21(WAF1/CIP1), undetectable in normal cells, was progressively induced in neoplastic cells and suppressed by NO-ASA up to PanIN3. Nuclear factor-kappaB activation, absent in normal tissue, increased progressively (17-fold in cancer); NO-ASA suppressed it throughout and significantly in PanIN1B and PanIN2. Cyclooxygenase-2 expression, absent during early stages, was induced 6-fold in carcinoma and suppressed by NO-ASA in PanIN3 and carcinoma. Conventional ASA had no effect on these molecular markers. Thus, NO-ASA profoundly prevented pancreatic cancer and modulated multiple molecular targets in this model system; conventional ASA had no such effects. NO-ASA merits further evaluation as a chemopreventive agent against pancreatic cancer.
AuthorsNengtai Ouyang, Jennie L Williams, George J Tsioulias, Jianjun Gao, Michael J Iatropoulos, Levy Kopelovich, Khosrow Kashfi, Basil Rigas
JournalCancer research (Cancer Res) Vol. 66 Issue 8 Pg. 4503-11 (Apr 15 2006) ISSN: 0008-5472 [Print] United States
PMID16618778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anticarcinogenic Agents
  • Carcinogens
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclooxygenase 2 Inhibitors
  • NF-kappa B
  • Nitric Oxide Donors
  • Nitrosamines
  • nitroxy-butyl-acetylsalicylic acid
  • nitrosobis(2-oxopropyl)amine
  • Cyclooxygenase 2
  • Aspirin
Topics
  • Animals
  • Anticarcinogenic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Aspirin (analogs & derivatives, pharmacology)
  • Carcinogens
  • Cell Growth Processes (drug effects)
  • Cricetinae
  • Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
  • Cyclooxygenase 2 (metabolism)
  • Cyclooxygenase 2 Inhibitors (pharmacology)
  • Disease Models, Animal
  • Female
  • Mesocricetus
  • NF-kappa B (metabolism)
  • Nitric Oxide Donors (pharmacology)
  • Nitrosamines
  • Pancreas (cytology, drug effects)
  • Pancreatic Neoplasms (chemically induced, pathology, prevention & control)

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