Nitric oxide–releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets
| Autor: | Bandaru S. Reddy, Barbara Simi, Levy Kopelovich, Vernon E. Steele, Chinthalapally V. Rao, Jagan M.R. Patlolla, Xiaoping Liu, Nengtai Ouyang, Basil Rigas, Chung Xiou Wang |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research Indoles Colorectal cancer Azoxymethane Nitric Oxide Synthase Type II Antineoplastic Agents Acetates Pharmacology Dinoprostone chemistry.chemical_compound medicine Carcinoma Animals Humans Prostaglandin E2 beta Catenin Aspirin biology Chemistry Nitric oxide synthase 2 medicine.disease Rats Inbred F344 Diet Rats Proliferating cell nuclear antigen Oncology Cyclooxygenase 2 Colonic Neoplasms Immunology Carcinogens biology.protein Arachidonic acid Cyclooxygenase medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 5:1530-1538 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-06-0061 |
| Popis: | Nitric oxide–releasing nonsteroidal anti-inflammatory drugs (NO-NSAID) are promising chemoprevention agents; unlike conventional NSAIDs, they seem free of appreciable adverse effects, while they retain beneficial activities of their parent compounds. Their effect on colon carcinogenesis using carcinoma formation as an end point is unknown. We assessed the chemopreventive properties of NO-indomethacin (NCX 530) and NO-aspirin (NCX 4016) against azoxymethane-induced colon cancer. Seven-week-old male F344 rats were fed control diet, and 1 week later, rats received two weekly s.c. injections of azoxymethane (15 mg/kg body weight). Two weeks after azoxymethane treatment, rats (48 per group) were fed experimental diets containing NO-indomethacin (0, 40, or 80 ppm), or NO-aspirin (1,500 or 3,000 ppm), representing 40% and 80% of the maximum tolerated dose. All rats were killed 48 weeks after azoxymethane treatment and assessed for colon tumor efficacy and molecular changes in colonic tumors and normally appearing colonic mucosa of different dietary groups. Our results suggest that NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly suppressed both tumor incidence (P < 0.01) and multiplicity (P < 0.001). The degree of inhibition was more pronounced with NO-indomethacin at both dose levels (72% and 76% inhibition) than with NO-aspirin (43% and 67%). NO-indomethacin at 40 and 80 ppm and NO-aspirin at 3,000 ppm significantly inhibited the colon tumors' (P < 0.01 to P < 0.001) total cyclooxygenase (COX), including COX-2 activity (52–75% inhibition) and formation of prostaglandin E2 (PGE2), PGF2α, and 6-keto-PGF1α, and TxB2 from arachidonic acid (53–77% inhibition). Nitric oxide synthase 2 (NOS-2) activity and β-catenin expression were suppressed in animals given NO-NSAID. In colonic crypts and tumors of animals fed these two NO-NSAIDs, there was a significant decrease in proliferating cell nuclear antigen labeling when compared with animals fed the control diet. The results of this study provide strong evidence that NO-NSAIDs possess strong inhibitory effect against colon carcinogenesis; their effect is associated with suppression of COX and NOS-2 activities and β-catenin levels in colon tumors. These results pave the way for the rational design of human clinical trials. [Mol Cancer Ther 2006;5(6):1530–8] |
| Databáze: | OpenAIRE |
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