| Cancer chemoprevention is a method of cancer control that uses natural or synthetic agents to block, retard, or even reverse the carcinogenic process. For example, induction of detoxication and cytoprotective enzymes can facilitate the elimination of carcinogens and provide protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by the reactive intermediates of carcinogens. The experiments described in this thesis seek to evaluate the chemopreventive potential of triterpenoids through activation of Nrf2 (NF-E2-related factor 2) signaling. In addition to conjugating and detoxication genes, Nrf2 regulates other cytoprotective mechanisms including antioxidative response, expression of the ubiquitin/proteasome system, the molecular chaperones/stress response system, and anti-inflammatory responses. For this reason, activation of Nrf2 signaling constitutes a broad protective response, making Nrf2 and its interacting partners ideal targets for cancer chemoprevention.;The chemopreventive efficacy of a synthetic oleanane triterpenoid, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), was evaluated in a rat model of aflatoxin-induced hepatic tumorigenesis. Pre-treatment with CDDO-Im produced an 85% reduction in hepatic preneoplastic lesions using an oral dose of 1 mumol/kg body weight and a greater than 99% reduction at 100 mumol/kg body weight. Furthermore, this protection was achieved in part through induction of Nrf2-regulated cytoprotective and detoxication enzymes.;A pharmacodynamic characterization of CDDO-Im and related triterpenoids was conducted to optimize their use in chemoprevention. These studies showed that CDDO-Im was widely distributed to many mouse tissues and very low oral doses (as low as 0.3 mumol/kg body weight) were required to induce Nrf2-regulated genes. Furthermore, several closely related triterpenoids were found to be extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex.;In order to gain insight into pathways affected by Nrf2 signaling, hepatic global gene expression changes induced by genetic activation of Nrf2 signaling in conditional Keap1 knockout mice were compared to pharmacologic activation using CDDO-Im. The results showed that genetic and pharmacologic activation of Nrf2 signaling modulated pathways beyond detoxication and cytoprotection, primarily genes associated with lipid metabolism. Additionally, analysis of pharmacologic activation with CDDO-Im suggested that Nrf2 is the primary mediator of CDDO-Im activity at this low dose relevant to chemoprevention. |
