cyclin-d1 and nitroaspirin

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.

Topics: Animals; Anticarcinogenic Agents; Aspirin; beta Catenin; Body Weight; Carcinoma in Situ; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Cyclin D1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Progression; Humans; Integrases; Male; Mice; Mice, Transgenic; Nitric Oxide Synthase Type II; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53

There is current evidence implicating the Wnt/beta-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57+/-4, 193+/-10 and >5000microM, and for transcriptional inhibition they were 12+/-1.8, 75+/-6.5 and >5000microM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular beta-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.

Topics: Anticarcinogenic Agents; Aspirin; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclooxygenase 2; DNA-Binding Proteins; Down-Regulation; Enzyme Induction; Female; Genes, Reporter; Humans; Inhibitory Concentration 50; Isomerism; Signal Transduction; Transcription Factor 4; Transcription Factors; Transcription, Genetic; Wnt Proteins

We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC50s for cell growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.

Topics: Activating Transcription Factor 2; Antineoplastic Agents; Aspirin; Cell Cycle; Cell Proliferation; Colonic Neoplasms; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Enzyme Activation; HT29 Cells; Humans; Inhibitory Concentration 50; Isomerism; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Nitric Oxide Donors; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-jun; RNA Interference; Signal Transduction; Structure-Activity Relationship; Time Factors; Transcription Factor AP-1