Nutritional-pharmacological combinations--a novel approach to reducing colon cancer incidence.

Abstract

Recent studies have suggested that n-9 fatty acids in olive oil prevent colon carcinogenesis while n-6 PUFA seems to activate this process. To evaluate the effects of nutritional-pharmacological combinations made up of olive or soy oil-based diets and the drug sulindac, on colon cancer incidence in a chemically induced (1,2-dimethylhydrazine, DMH) rat cancer model. Male rats were assigned to two different dietary regimes based on a standard murine defined diet (AIN-76A) containing either a low (4%) or high (15 %) concentration of olive or soy oil. Some groups also received sulindac in their food (80 mg/kg food) starting from the ninth week following the first DMH or vehicle administration. Oleic and linoleic acid reached higher levels in plasma and liver lipids when rats were fed high concentrations of olive or soy oil, respectively. Rats fed a low or high soy oil-based diet showed no significant difference in the number of aberrant crypt foci (ACF) in proximal or distal colon specimens. In contrast, rats fed a higher olive oil-based diet developed a significantly lower number of ACF than rats fed a low concentration of olive oil. Addition of sulindac reduced the number of ACF in rats fed the 4%, but not the 15%, soy oil diet. In contrast, the effect of sulindac was significant when combined with both the low and high concentrations of olive oil. High soy oil-based diet or DMH treatment upregulated colon expression of Bcl-2, but not that of cyclooxygenase-2 (COX-2). In contrast, olive oil dose-dependently downregulated the expression of both Bcl-2 and COX-2 in colonic mucosa and also abrogated the upregulation of Bcl-2 by DMH. Olive oil/sulindac combinations were effective in downregulating colonic mucosa Bcl-2 expression (with the 4% oil diet) and COX-2 expression (with the 15% oil diet). These effects were not observed in rats fed the soy oil/sulindac combinations. Caspase-3 activity in colonic mucosa was unaffected by soy oil or soy oil/sulindac combinations. The addition of olive oil, on the other hand, significantly enhanced colonic caspase-3 activity. Diets containing high levels of olive oil exert a significant protective effect from tumor development that is additive with the inhibitory effect of sulindac. These inhibitory effects are mediated by regulating the expression and activity of key proteins involved in prostaglandin-biosynthesis and apoptosis-induction pathways. It may be concluded that appropriate dietary-pharmacological combination can improve anti-tumor efficacy over either dietary or pharmacological intervention alone.