Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of CRC has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects. Novel compounds which are rational modifications of well-established chemopreventive agents and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. Recently, we developed highly innovative orally bioavailable hybrid molecule, p-XS- Asp, designed by conjugating two well-known chemopreventive agents i.e. 1,4-phenylene-bis(methylene)- selenocyanate (p-XSC) and nonsteroidal anti-inflammatory drug aspirin, as potential agents for CRC prevention. Both p-XSC and aspirin have shown promise as CRC chemopreventives. The advantage of the hybrid agent is two-fold: (i) the combined p-XSC-Asp would generate the active p-XSeH putative metabolite similar to p-XSC but without the toxicity related to hydrogen cyanide (HCN), that is released as a side product on p-XSC metabolism but would not form in p-XS-Asp metabolism, and (ii) the novel agent would function through releasing aspirin, thus enhancing the overall chemopreventive efficacy of the hybrid molecule. The overall goal of this project is to validate the potential of p-XS-Asp as colon cancer chemopreventive agent. We hypothesize that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but aspirin, thus making it less toxic and more potent than p-XSC or aspirin alone.
The specific aims are to: 1. Determine the chemopreventive efficacy of p-XS-Asp in the F344 rat model of colorectal carcinogenesis;and 2. Evaluate the mechanism of action(s) associated with chemopreventive effects of p-XS-Asp in AOM-induced carcinogenesis. We will use the experimental approach of evaluating effectiveness of p-XS-Asp for inhibiting development of aberrant crypt foci (ACF) in F344 rats injected s.c. with AOM, once weekly for 2 weeks, at a dose rate of 15 mg/kg body weight per week. Furthermore, to begin establishing the mechanism, we will carry out metabolism of p-XS-Asp using rat liver microsomes, and evaluate its effect, relative to p-XSC and aspirin, on markers of apoptosis and cell proliferation, signaling pathways such as PI3K/AKT and MAPK, NF-kB and expression of COX-1 and COX-2 in colorectal tissues, and determine the plasma PGE2 levels of rats from different treatment groups. These studies will begin establishing the potential of p-XS-Asp as a colorectal cancer preventive agent. Long term, validation of p-XS-Asp as an effective and safe agent would reduce the chances of developing colorectal cancer thereby directly decreasing the mortality incidence.
To date, there are no effective agents available for the prevention of colorectal cancer (CRC). The studies proposed here, will initiate validation of our recently developed hybrid agent p-XS-Asp as a potent and safe chemopreventive against AOM induced carcinogenesis and begin elucidating underlying mechanism of chemoprevention. If effective, this study would reveal a promising agent which, in near future, could prove capable of preventing CRC development in humans.
