Nitric oxide-releasing aspirin (
NO-aspirin) represents a novel class of promising chemopreventive agents. Unlike conventional nonsteroidal anti-inflammatory drugs,
NO-aspirin seems to be free of adverse effects while retaining the beneficial activities of its parent compound. The effect of
NO-aspirin on pancreatic
carcinogenesis was investigated by assessing the development of precursor pancreatic lesions and
adenocarcinomas in Kras(G12D/+) transgenic mice that recapitulate human
pancreatic cancer progression. Six-week-old male p48(Cre/+)-LSL-Kras(G12D/+) transgenic mice (20 per group) were fed diets containing 0, 1000, or 2000 ppm
NO-aspirin. The development of pancreatic
tumors was monitored by positron emission tomography imaging. All mice were killed at the age of 41 weeks and assessed for pancreatic intraepithelial
neoplasia (PanIN) and pancreatic ductal
adenocarcinoma (PDAC) and for molecular changes in the
tumors. Our results reveal that
NO-aspirin at 1000 and 2000 ppm significantly suppressed pancreatic
tumor weights, PDAC incidence, and
carcinoma in situ (PanIN-3 lesions). The degree of inhibition of PanIN-3 and
carcinoma was more pronounced with
NO-aspirin at 1000 ppm (58.8% and 48%, respectively) than with 2000 ppm (47% and 20%, respectively).
NO-aspirin at 1000 ppm significantly inhibited the spread of
carcinoma in the pancreas (∼97%; P < .0001). Decreased expression of
cyclooxygenase (COX; with ∼42% inhibition of total COX activity),
inducible nitric oxide synthase,
proliferating cell nuclear antigen, Bcl-2,
cyclin D1, and β-
catenin was observed, with induction of p21, p38, and p53 in the pancreas of
NO-aspirin-treated mice. These results suggest that low-dose
NO-aspirin possesses inhibitory activity against pancreatic
carcinogenesis by modulating multiple molecular targets.