Colorectal cancer chemoprevention with phytochemical combinations

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DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is highly prevalent worldwide and exhibits high mortality. Active dietary chemicals are currently being explored as complementary cancer preventive agents in clinical trials. Our long-term goal is to elucidate the impact of metabolism on the pharmacokinetics and associated clinical efficacy of promising phytochemicals. Importantly, while combinations of phytochemicals are increasingly shown to be more efficacious than single agents alone, mechanisms underlying this synergy are not understood. Specifically, there is no research to date on how dietary phytochemical combinations modulate glucuronidating enzymes - i.e. uridine diphosphoglucuronosyltransferases (mammalian UGT; human UGT, mouse ugt). This proposal is based on the hypothesis that phytochemical combinations synergistically induce mammalian UGTs. Phytochemical combinations might thus more effectively inactivate carcinogens than single agents. Toward this, two specific aims are proposed: 1) Evaluate UGT induction by phytochemicals alone and in combination. Phytochemical combinations trans-resveratrol + curcumin and trans-resveratrol + chrysin in ratios based on individual antiproliferative IC50s will be tested and compared against each phytochemical alone. Induction of human UGTs will be evaluated in transformed human intestinal Caco-2 cells, while mouse ugts will be evaluated in mouse intestine epithelial normal and preneoplastic (YAMC and IMCE) cells, as well as mouse hepatic ImHep cells. Combinations that yield most significant results in part A above will be tested in vivo in a normal C57BL mouse model. 2) Evaluate UGT induction as a mechanism for chemoprevention by phytochemical combinations. Whether synergistic UGT induction by phytochemical combinations is a mechanism for enhanced chemoprevention will be evaluated in mice. Combinations with the highest predicted efficacy from Aim 1 will be tested in a dextran sulfate sodium + 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (DSS/PhIP) colon adenocarcinoma mouse model, and aberrant crypt foci (ACF), tumor size/frequency, and ugt induction will be measured. Chemopreventive efficacy will be compared against that of Celecoxib, a known CRC preventive agent. Data from the proposed aims will form the basis of future studies to evaluate additional metabolizing enzymes and transporters that are modulated by phytochemicals.