COX-2 Inhibitor and N-3PUFA in Colon Cancer Prevention
Principal Investigator: Bandaru Reddy
Abstract: The long-term objective of our research is to identify innovative strategies for colon cancer prevention and to apply the knowledge from preclinical efficacy studies to use with individuals at high-risk for colon cancer as a means of prevention. Current evidence suggests that a diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs) and cyclooxygenase (COX)-2 inhibitors, such as celecoxib suppress azoxymethane (AOM)-induced colon carcinogenesis in F344 rats. Although colon tumor inhibition by COX-2 inhibitors is much more effective than traditional NSAIDs, high doses of COX-2 inhibitors have caused some side effects in humans. The preclinical experiments proposed in this application will provide compelling evidence that the aggregate action of n-3 PUFA-rich diet in combination with a COX-2 inhibitor, celecoxib would be significant, while side effects induced by the COX-2 inhibitor would be minimized. The proposed studies will evaluate two hypothesis: a) There is synergism in the mechanisms of action of COX-2 inhibitors and n-3 PUFAs, the former inhibiting carcinogenesis through modulation of generation of eicosanoids, angiogenesis and apoptosis while the latter suppressing colon carcinogenesis through NO pathways, cell differentiation and apoptosis, b) the combination of a diet rich in n-3 PUFAs with a COX-2 inhibitor will increase the efficacy by modulating synergistically the above molecular parameters. The specific aims are: 1) Determine the efficacy of a low dose of celecoxib administered in n-3 PUFA rich diet as compared when a high dose of this agent administered in a high-fat, Western style diet containing mixed lipids in AOM-induced colon carcinogenesis in F344 rats. 2) Determine the combined effects of celecoxib administered in n-3 PUFA-rich diet on colon cancer-related genes in colonic mucosa and tumors of rats. We will focus on apoptotic genes, Bcl-2, NF?B and on the eicosanoid- and NO-pathways including COX-2, LOX, and iNOS and their interactions with other functional groups of genes in colon carcinogenesis using DNA microarrays, RT-PCR and Western Blot analysis. Clear delineation of the synergistic effects in preclinical models will allow the rational design of human clinical trials.
Funding Period: 1993-09-30 - 2009-04-30
more information: NIH RePORT
- Chemoprophylaxis of colon cancerBandaru S Reddy
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Curr Gastroenterol Rep 7:389-95. 2005....
- Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 ratsBandaru S Reddy
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA
Cancer Res 66:4542-6. 2006..These observations are of clinical significance because this can pave the way for the use of combinations of these agents in small doses against colon cancer...
- Strategies for colon cancer prevention: combination of chemopreventive agentsBandaru S Reddy
Susan Lehman Cullman Laboratory for Cancer Research, USA
Subcell Biochem 42:213-25. 2007....
- Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cellsHang Xiao
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Int J Cancer 122:2115-24. 2008..The present work suggests the possible therapeutic application of this combination and provides leads for mechanistic and biomarker investigations in clinical trials...
- Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023Karen Kelly
University of Kansas Medical Center, Kansas City, KS 66160, USA
J Clin Oncol 26:2450-6. 2008..Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non-small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease...
- Effects of combination of calcium and aspirin on azoxymethane-induced aberrant crypt foci formation in the colons of mice and ratsYingying Liu
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 8020, USA
Nutr Cancer 60:660-5. 2008..These results indicate that the combination of calcium and aspirin did not produce a synergistic effect on the ACF formation in AOM-treated mice and rats...