An extensive body of work supports a fundamental link between inflammation and a number of diseases, particularly cancer. Synthetic oleanane triterpenoids have been shown in preclinical models to be potent in the prevention of cancer driven by chronic inflammation. A central premise of the proposed work is that the oleanane triterpenoids are representative of a much larger class of anti-inflammatory/anti-cancer triterpenoids. We hypothesize that exploration of diverse triterpenoids, will allow a careful dissection of the molecular pathways behind triterpenoid chemoprevention, and will define novel classes of potent and effective cancer chemopreventive agents. To study the chemical space around the triterpenoids we will use two approaches including: 1) a novel oxidative cleavage and skeletal rearrangement;and 2) an innovative natural product isolation strategy to identify novel triterpenoids. These molecules will then be evaluated in vitro for their ability to suppress expression of key inflammatory mediators, and in vivo for their ability to suppress progression of gastrointestinal carcinogenesis in a system that couples immune mediated induction of oncogenic signaling intermediates with loss of expression of important tumor suppressor pathways.
This project represents a collaborative endeavor between a two investigators interested in triterpenoids as cancer chemopreventives. The described aims will synthesize and isolate known and novel triterpenoids from traditional medicine sources to be tested as chemopreventives in inflammation driven models of carcinogenesis.
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