Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma.

PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis. EXPERIMENTAL DESIGN: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. RESULTS: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. CONCLUSION: The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Pterostilbene, an active constituent of blueberries, suppresses aberrant crypt foci formation in the azoxymethane-induced colon carcinogenesis model in rats.

PURPOSE: Epidemiologic studies have linked the consumption of fruits and vegetables to reduced risk of several types of cancer. Laboratory animal model studies have provided evidence that stilbenes, phenolic compounds present in grapes and blueberries, play a role in inhibiting the risk of certain cancers. Pterostilbene, a naturally occurring stilbene from blueberries, was tested for its preventive activity against colon carcinogenesis. EXPERIMENTAL DESIGN: Experiments were designed to study the inhibitory effect of pterostilbene against the formation of azoxymethane-induced colonic aberrant crypt foci (ACF) preneoplastic lesions in male F344 rats. Beginning at 7 weeks of age, rats were treated with azoxymethane (15 mg/kg body weight s.c., once weekly for 2 weeks). One day after the second azoxymethane treatment, rats were fed experimental diets containing 0 or 40 ppm of pterostilbene. At 8 weeks after the second azoxymethane treatment, all rats were sacrificed, and colons were evaluated for ACF formation and for inhibition of inducible nitric oxide synthase (iNOS) and proliferating cell nuclear antigen. Effects on mucin MUC2 were also determined. RESULTS: Administration of pterostilbene for 8 weeks significantly suppressed azoxymethane-induced formation of ACF (57% inhibition, P < 0.001) and multiple clusters of aberrant crypts (29% inhibition, P < 0.01). Importantly, dietary pterostilbene also suppressed azoxymethane-induced colonic cell proliferation and iNOS expression. Inhibition of iNOS expression by pterostilbene was confirmed in cultured human colon cancer cells. CONCLUSIONS: The results of the present study suggest that pterostilbene, a compound present in blueberries, is of great interest for the prevention of colon cancer.