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.
| Janakiram, Naveena B; Mohammed, Altaf; Madka, Venkateshwar et al. (2016) Prevention and treatment of cancers by immune modulating nutrients. Mol Nutr Food Res 60:1275-94 |
| Janakiram, Naveena B; Mohammed, Altaf; Bryant, Taylor et al. (2015) Improved innate immune responses by Frondanol A5, a sea cucumber extract, prevent intestinal tumorigenesis. Cancer Prev Res (Phila) 8:327-37 |
| Janakiram, Naveena B; Mohammed, Altaf; Zhang, Yuting et al. (2013) Chemopreventive efficacy of raloxifene, bexarotene, and their combination on the progression of chemically induced colon adenomas to adenocarcinomas in rats. Cancer Prev Res (Phila) 6:1251-61 |
| Janakiram, Naveena B; Rao, Chinthalapally V (2012) iNOS-selective inhibitors for cancer prevention: promise and progress. Future Med Chem 4:2193-204 |
| Janakiram, Naveena B; Rao, Chinthalapally V (2012) Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors. For Immunopathol Dis Therap 3:155-167 |
| Mohammed, Altaf; Qian, Li; Janakiram, Naveena B et al. (2012) Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice. Int J Cancer 131:1951-62 |
| Janakiram, Naveena B; Mohammed, Altaf; Qian, Li et al. (2012) Chemopreventive effects of RXR-selective rexinoid bexarotene on intestinal neoplasia of Apc(Min/+) mice. Neoplasia 14:159-68 |
| Janakiram, N B; Mohammed, A; Bronze, M S et al. (2012) Prophylactic vaccine approach for colon and pancreatic cancers: present and future. Curr Med Chem 19:3664-78 |
| Rao, Chinthalapally V; Kurkjian, Carla D; Yamada, Hiroshi Y (2012) Mitosis-targeting natural products for cancer prevention and therapy. Curr Drug Targets 13:1820-30 |
| Rao, Chinthalapally V; Janakiram, Naveena B; Mohammed, Altaf (2012) Lipoxygenase and Cyclooxygenase Pathways and Colorectal Cancer Prevention. Curr Colorectal Cancer Rep 8:316-324 |
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