title: Inhibition of pancreatic intraepithelial neoplasia progression to carcinoma by nitric oxide-releasing aspirin in p48(Cre/+)-LSL-Kras(G12D/+) mice.
abstract: 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.
authors.affiliation: Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, Peggy and Charles Stephenson Cancer Center, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. cv-rao@ouhsc.edu
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Ritchie
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.forename: Awasthi
authors.initials: A
authors.lastname: Vibhudutta
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001241:Aspirin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000819:agonists / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000819:agonists; D051176:beta Catenin / Q000037:antagonists & inhibitors
chemical_list: D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C102148:nitroaspirin; D001241:Aspirin