Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model.
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.
Ouyang
Nengtai
N
Division of Cancer Prevention, State University of New York at Stony Brook, Stony Brook, New York 11794-5200, USA.
Williams
Jennie L
JL
Tsioulias
George J
GJ
Gao
Jianjun
J
Iatropoulos
Michael J
MJ
Kopelovich
Levy
L
Kashfi
Khosrow
K
Rigas
Basil
B
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002273:Carcinogens; D048708:Cell Growth Processes / Q000187:drug effects; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008647:Mesocricetus; D016328:NF-kappa B / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009602:Nitrosamines; D010179:Pancreas / Q000166:cytology / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009602:Nitrosamines; C098312:nitroxy-butyl-acetylsalicylic acid; C013622:nitrosobis(2-oxopropyl)amine; D051546:Cyclooxygenase 2; D001241:Aspirin