Apigenin and naringenin favorably modulate aberrant crypt foci development and colonic cell cytokinetics

B135

Evidence suggests that a diet abundant in fruits and vegetables may be protective against colon cancer development, in part through inhibition of pro-inflammatory processes. Bioactive compounds in citrus, such as flavonoids and limonoids, possess anti-tumorigenic effects in various models of cancer, therefore, the potential protective effects of four citrus flavonoids and one limonoid mixture were investigated in the chemically induced rat colon cancer model. Male SD rats (n =60; 10 rats/group) received diets containing 0.1% apigenin, 0.02% naringenin, 0.1% hesperidin, 0.01% nobiletin, 0.035% limonin glucoside/obacunone glucoside mixture, or a control diet (0% flavonoid/limonoid). Rats received the diets for 10 wk and were injected with azoxymethane (15 mg/kg body weight) at wk 3 and 4. The excised colons were evaluated for aberrant crypt foci (ACF) formation, cell proliferation (PCNA assay), apoptosis (TUNEL assay), and iNOS and COX-2 expression (immunoblot). When compared to the control diet, apigenin lowered the number of high multiplicity ACF (> 4 AC/focus) by 57% (P<0.05) and tended to lower the proliferative index (by 28%; P=0.07). Relative to control, naringenin lowered (P < 0.05) the number of high multiplicity ACF by 51%, the proliferative index by 32%, and reduced (P < 0.05) the expansion of the proliferative zone. Both apigenin and naringenin increased apoptosis of surface colon cells (by 78% and 97%, respectively; P<0.05) when compared to the control diet. There were no significant effects of hesperidin, nobiletin, or the limonin glucoside/obacunone glucoside mixture on any of the variables. Colonic mucosal protein levels of iNOS or COX-2 were not different among the six diet groups. The ability of apigenin and naringenin to reduce high multiplicity ACF through changes in colon cytokinetics involves mechanisms other than suppression of the pro-inflammatory iNOS and COX-2 proteins. Funded by THECB (003658-0359c-2001 and 010366-0194-2001), USDA/CSREES 2005-34402-16401, and NIEHS P30-ES09106.