PREVENTION OF COLORECTAL CANCER BY iNOS AND COX-2 SELECTIVE INHIBITORS

Summary

Principal Investigator: CHINTHALAPALLY RAO
Abstract: The overall objective of this proposal is to develop the use of inducible nitric oxide synthase (iNOS)-selective inhibitors in the chemoprevention of colorectal cancer, and to gain an understanding of the cellular and molecular mechanism(s) of tumor inhibition by these agents. In addition, we will design the strategies for improving the efficacy of colon cancer prevention and treatment by concurrent application of iNOS- and COX-2 selective inhibitors. Colorectal cancer is one of the most common human malignancies in the United States, anticipated to account for 140,000 new cases and about 56,000 deaths in the year 2003. Developing treatment strategies, aimed at a specific molecular target that facilitate(s) tumor cell growth, uncontrolled expansion and invasion, provide a rational approach. Nitric oxide, produced by isoforms of NOS, has been implicated in several pathophysiological conditions including colon carcinogenesis. Our studies and those of others indicate that iNOS activities were up-regulated several-fold in colon tumors compared to normal mucosa and, importantly, nitric oxide or its reactive molecules derived from these enzymes play a pivotal role in modulation of apoptosis and proliferation. Recent evidence from our laboratory suggests that iNOS-selective inhibitors suppress chemically-induced colon carcinogenesis and also tumor formation in transgenic APC min mice. Thus, it is important to systematically develop iNOS-selective inhibitors for colon cancer prevention/treatment and delineate the specific mechanisms that lead to inhibition of tumorigenesis by these agents. Specifically, we will 1) examine the chemopreventive efficacy of different iNOS-inhibitors [PBIT, NILT and BIPPA] on azoxymethane (AOM)-induced colon carcinogenesis in rats (maximum tolerated dose selection; dose-response effects; and effectiveness during promotion/progression stages of colon carcinogenesis; 2) establish strategies to improve efficacy of colon cancer prevention and treatment by a combination of COX-2- and iNOS-selective inhibitors and 3) assess the cellular and molecular biomarkers associated with iNOS inhibition/COX-2 inhibition (apoptotic and proliferation changes, nitric oxide, 3-nitrotyrosine, and expression and activities of isoforms of NOS and COX) and study the modulation of gene expression profiles to identify changes in functional groups of genes associated with apoptosis, cell-cycle regulation and iNOS and COX-2 mediated signals and 4) understand the mechanisms by which inhibitors of iNOS and COX-2 modulate colon tumor cell proliferation and apoptosis.
Funding Period: 2004-09-23 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets
    Chinthalapally V Rao
    Department of Medicine, Hem Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Mol Cancer Ther 5:1530-8. 2006
  2. pmc iNOS-selective inhibitors for cancer prevention: promise and progress
    Naveena B Janakiram
    Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
    Future Med Chem 4:2193-204. 2012
  3. ncbi Mitosis-targeting natural products for cancer prevention and therapy
    Chinthalapally V Rao
    Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center OUHSC, Oklahoma City, 73104, USA
    Curr Drug Targets 13:1820-30. 2012
  4. ncbi Prophylactic vaccine approach for colon and pancreatic cancers: present and future
    N B Janakiram
    Center for Chemoprevention and Cancer Drug Development, 975 NE 10th Street, BRC 1205, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Curr Med Chem 19:3664-78. 2012
  5. pmc Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice
    Naveena B Janakiram
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem Onc Section, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    Neoplasia 14:159-68. 2012
  6. pmc Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice
    Altaf Mohammed
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem Onc Section, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    Int J Cancer 131:1951-62. 2012
  7. ncbi Cancer stem cell markers as potential targets for epithelial cancers
    Venkateshwar Madka
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Oklahoma City, OK, USA
    Indian J Exp Biol 49:826-35. 2011
  8. ncbi Genes that modulate the sensitivity for anti-microtubule drug-mediated chemotherapy
    H Y Yamada
    Department of Medicine, Hematology Oncology Section, University of Oklahoma Health Sciences Center OUHSC, Oklahoma City, OK 73104, USA
    Curr Cancer Drug Targets 10:623-33. 2010
  9. pmc Inhibition of azoxymethane-induced colorectal cancer by CP-31398, a TP53 modulator, alone or in combination with low doses of celecoxib in male F344 rats
    Chinthalapally V Rao
    Department of Medicine, Hem Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Cancer Res 69:8175-82. 2009
  10. ncbi Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer
    Naveena B Janakiram
    Department of Medicine, Hem Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Curr Mol Med 9:565-79. 2009

Detail Information

Publications13

  1. ncbi Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets
    Chinthalapally V Rao
    Department of Medicine, Hem Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Mol Cancer Ther 5:1530-8. 2006
    ..These results pave the way for the rational design of human clinical trials...
  2. pmc iNOS-selective inhibitors for cancer prevention: promise and progress
    Naveena B Janakiram
    Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
    Future Med Chem 4:2193-204. 2012
    ..Here, we review iNOS expression, generation of NO, involvement of NO in altering signaling pathways, and iNOS select inhibitors and their possible use for the prevention and treatment of various cancers...
  3. ncbi Mitosis-targeting natural products for cancer prevention and therapy
    Chinthalapally V Rao
    Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center OUHSC, Oklahoma City, 73104, USA
    Curr Drug Targets 13:1820-30. 2012
    ..These advances help us to identify and develop potential natural agents for the prevention and treatment of cancer. This review will focus on natural products that target mitotic process and/or proteins involved in mitotic progression...
  4. ncbi Prophylactic vaccine approach for colon and pancreatic cancers: present and future
    N B Janakiram
    Center for Chemoprevention and Cancer Drug Development, 975 NE 10th Street, BRC 1205, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Curr Med Chem 19:3664-78. 2012
    ..Preclinical and early clinical trials incorporating these principles are discussed...
  5. pmc Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice
    Naveena B Janakiram
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem Onc Section, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    Neoplasia 14:159-68. 2012
    ..01). Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%-72%, P < .0001) and inflammatory cytokines...
  6. pmc Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice
    Altaf Mohammed
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem Onc Section, PC Stephenson Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    Int J Cancer 131:1951-62. 2012
    ....
  7. ncbi Cancer stem cell markers as potential targets for epithelial cancers
    Venkateshwar Madka
    Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Oklahoma City, OK, USA
    Indian J Exp Biol 49:826-35. 2011
    ..In this review, we attempt to define various potential markers of cancer stem cells and potential exploration as therapeutic targets for epithelial cancer prevention and treatment...
  8. ncbi Genes that modulate the sensitivity for anti-microtubule drug-mediated chemotherapy
    H Y Yamada
    Department of Medicine, Hematology Oncology Section, University of Oklahoma Health Sciences Center OUHSC, Oklahoma City, OK 73104, USA
    Curr Cancer Drug Targets 10:623-33. 2010
    ..Understanding signaling pathways involved in drug efficacy will aid to rationally develop synergistic chemotherapy strategy...
  9. pmc Inhibition of azoxymethane-induced colorectal cancer by CP-31398, a TP53 modulator, alone or in combination with low doses of celecoxib in male F344 rats
    Chinthalapally V Rao
    Department of Medicine, Hem Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Cancer Res 69:8175-82. 2009
    ....
  10. ncbi Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer
    Naveena B Janakiram
    Department of Medicine, Hem Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Curr Mol Med 9:565-79. 2009
    ..In this review, we explore the mechanisms that trigger formation of LXs and Rvs, to highlight the relative importance of LXs and Rvs in carcinogenesis in relation to pro-inflammatory mediators...
  11. pmc Curcumin protects retinal cells from light-and oxidant stress-induced cell death
    Md Nawajes A Mandal
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA
    Free Radic Biol Med 46:672-9. 2009
    ....