COX-2 Inhibitor and N-3PUFA in Colon Cancer Prevention

Summary

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

Top Publications

  1. ncbi Chemoprophylaxis of colon cancer
    Bandaru 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
  2. ncbi Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats
    Bandaru 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
  3. ncbi Strategies for colon cancer prevention: combination of chemopreventive agents
    Bandaru S Reddy
    Susan Lehman Cullman Laboratory for Cancer Research, USA
    Subcell Biochem 42:213-25. 2007
  4. ncbi Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells
    Hang 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
  5. ncbi Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023
    Karen Kelly
    University of Kansas Medical Center, Kansas City, KS 66160, USA
    J Clin Oncol 26:2450-6. 2008
  6. ncbi Effects of combination of calcium and aspirin on azoxymethane-induced aberrant crypt foci formation in the colons of mice and rats
    Yingying 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

Scientific Experts

  • Bandaru Reddy
  • Karen Kelly
  • Hang Xiao
  • Yingying Liu
  • Chung S Yang
  • Qiang Zhang
  • Harold Newmark
  • Mou Tuan Huang
  • Xingpei Hao
  • Barbara Simi
  • Yong Lin
  • Jihyeung Ju

Detail Information

Publications6

  1. ncbi Chemoprophylaxis of colon cancer
    Bandaru 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
    ....
  2. ncbi Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats
    Bandaru 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...
  3. ncbi Strategies for colon cancer prevention: combination of chemopreventive agents
    Bandaru S Reddy
    Susan Lehman Cullman Laboratory for Cancer Research, USA
    Subcell Biochem 42:213-25. 2007
    ....
  4. ncbi Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells
    Hang 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...
  5. ncbi Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023
    Karen 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...
  6. ncbi Effects of combination of calcium and aspirin on azoxymethane-induced aberrant crypt foci formation in the colons of mice and rats
    Yingying 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...