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Combination Regimens Using Dietary Components For The Chemoprevention Of Colorectal Cancer and Inflammation

ABSTRACT COMBINATION REGIMENS USING DIETARY COMPONENTS FOR THE CHEMOPREVENTION OF COLORECTAL CANCER AND INFLAMMATION September 2018 CHRISTINA DIMARCO-CROOK, B.S., IMMACULATA UNIVERSITY M.S., DREXEL UNIVERSITY Ph.D., UNIVERSITY OF MASSACHUSETTS AMHERST Directed by: Professor Hang Xiao Dietary components have been found to effectively modulate multiple deregulated signaling pathways associated with the initiation and progression of carcinogenesis and inflammation in cellular and animal models. However, clinical studies have shown mixed results when examining the efficacy of individual dietary components, perhaps suggestive of the synergism that exists between multiple components within a particular food and the diet as a whole. Additional research is needed to identify and characterize the unknown interactions and potential chemopreventive and anti-inflammatory properties within combination regimens using dietary components. Nobiletin a polymethoxyflavone (PMF) found primarily in the peel of sweet (C. sinensis) and bitter (C. aurantium) orange has demonstrated significant anti-cancer and anti-inflammatory effects in both cellular and animal models of colon cancer; therefore it is important to investigate the biological activities and interactions of its metabolites with other dietary components in order to better understand the possible mechanisms of nobiletin in vivo. One of the primary metabolites of nobiletin in the mouse 3',4'-didemethylnobiletin (DDMN), has been identified as the metabolite with the strongest anti-proliferative effects in HCT116 wild-type p53 colon cancer cells. Colonic concentration of nobiletin in the mouse is also much lower than its primary metabolites, of which DDMN is reported to exhibit stronger anti-cancer and anti-inflammatory effects than its parent compound nobiletin. In addition, curcumin, apigenin and luteolin have each been shown individually to exhibit significant anti-carcinogenic and anti-inflammatory effects in various colon cancer model systems; however the interaction of these dietary components in combination with DDMN has yet to be explored. Our results find for the first time apigenin or luteolin, two flavones though similar in structure, to have strikingly different responses when combined with DDMN in HCT116 wild-type p53 colon cancer cells. Apigenin and DDMN are additive in combination with no apparent interaction whereas luteolin when combined with DDMN exhibits an antagonistic response with diminished anti-proliferative effects. Remarkably, in sharp contrast to these findings the combination of curcumin and DDMN in HCT116 wild-type p53 colon cancer cells demonstrates strong synergism with enhanced anti-proliferative effects which greatly exceed the effects of individual treatments. Additional examination of the synergistic combination of curcumin and DDMN reveals significant cell cycle arrest and extensive apoptosis induced by the combination, which were much stronger than the effects induced by the treatments with curcumin or DDMN alone. Proteins associated with cell cycle arrest and apoptosis were analyzed by Western Blot to confirm the change in expression of these proteins were much greater in response to the combination treatment of curcumin and DDMN than each compound alone. The synergy between curcumin and DDMN offers a possible novel mechanism for nobiletin in combination with curcumin and warrants further investigation on their combination to determine its chemopreventive and anti-inflammatory potential for colon cancer in vivo.
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