Overall goal of our study is to evaluate the chemopreventive efficacy of Secoxib-1 GSH, a newly developed selenium analog of Celecoxib, against colon cancer. Cancer is the second leading cause of death among Americans. Conversion of normal colonic cells to malignant lesions requires several steps and often proceeds over considerable time periods, on average, 10-15 years, thus providing a window of opportunity for effective intervention and prevention. However, in 2012 it was estimated that in the United States alone about 150,000 people will be diagnosed with colorectal cancer. Earlier reports have established cyclooxygenase (COX) as an important molecular target for mechanistic studies and important target for new anticancer drugs screening. The long-term uses of COX selective inhibitor (COXIBs), a class of compounds that are selective COX-2 inhibitors, have shown cardio-toxic side effects. Therefore, there is an urgent need for the development of new agents for the prevention modality of colon cancer. In this revised application, we will investigate the inhibitory effects of Secoxib-1GSH, a newly developed selenium analog of Celecoxib, against colon cancer. In our preliminary studies, Secoxib-1 GSH has retained the selective shown protective effect to these cells. We hypothesize that Secoxib-1 GSH, having minimal or no cardio-toxicity; having inhibitory effects on multiple mechanistic pathways including inhibition of COX-2, PI3K/Akt, and NFkB will be a safe and potent chemopreventive agent for prevention of colon cancer. To test our hypothesis, we propose to determine maximum tolerated dose (MTD) of Secoxib-1 GSH when fed in the diet to male F344 rats for the assessment of major organ related systemic toxicity. Based on the outcome from the MTD study, we will examine and compare the inhibitory potency of Secoxib-1 GSH with Celecoxib in male F344 rats against 1, 2-Dimethylhydrazine (DMH) induced mucin depleted foci (MDF), colonic aberrant crypt foci (ACF), preneoplastic lesions; and tumor burden in rats. We will also examine the effects of Secoxib-1 GSH on the important mechanistic pathways of colon cancer in the MDF, ACF, and tumor samples from male F344 rats.
The primary objective is to investigate the beneficial effects of a combination of selenium, an essential micronutrient, having minimal or no undesired cardio-toxicity, and inhibition of mechanistic pathways that are critical for colon cancer. A chemopreventive approach proposed here has significant potential for prevention of colon cancer and that will establish the basis for long term bioassay and for future clinical trials in human.
