Diets containing freeze-dried black raspberries (BRB) suppress the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. Using bioassay-directed fractionation, the anthocyanins in BRB were found to be the most active constituents for down-regulation of carcinogen-induced nuclear factor-κB and activator protein-1 expression in mouse epidermal cells in vitro. The present study was undertaken, therefore, to determine if the anthocyanins contribute to the chemopreventive activity of BRB in vivo. F344 rats consumed diets containing either (a) 5% whole BRB powder, (b) an anthocyanin-rich fraction, (c) an organic solvent-soluble extract (a-c each contained ∼3.8 μmol anthocyanins/g diet), (d) an organic-insoluble (residue) fraction (containing 0.02 μmol anthocyanins/g diet), (e) a hexane extract, and (f) a sugar fraction (e and f had only trace quantities of anthocyanins), all derived from BRB. Animals were fed diets 2 weeks before treatment with NMBA and throughout the bioassay. Control rats were treated with NMBA only. Animals were killed at week 30, and esophageal tumors were enumerated. The anthocyanin treatments (diet groups a-c) were about equally effective in reducing NMBA tumorigenesis in the esophagus, indicating that the anthocyanins in BRB have chemopreventive potential. The organic-insoluble (residue) fraction (d) was also effective, suggesting that components other than berry anthocyanins may be chemopreventive. The hexane and sugar diets were inactive. Diet groups a, b, and d all inhibited cell proliferation, inflammation, and angiogenesis and induced apoptosis in both preneoplastic and papillomatous esophageal tissues, suggesting similar mechanisms of action by the different berry components.Esophageal cancer is the third most common gastrointestinal malignancy (1) and the sixth most frequent cause of cancer death in the world (2). Squamous cell carcinoma is the predominant histologic subtype worldwide, and persons with this disease have a high rate of mortality (3). It has been estimated that more than two thirds of human cancer can be prevented through appropriate lifestyle modifications (4). Although Doll and Peto (5) reported that ∼35% of human cancer mortality is caused by diet, more than 250 population-based studies, including case-control and cohort studies, indicate that persons who eat about five servings of fruit and vegetables per day have approximately half the risk of developing cancer-particularly cancers of the digestive and respiratory tracts-than do those who eat fewer than two servings per day (4). Chemoprevention can play an integral role in the overall strategy of reducing the incidence of cancer and is a potentially viable approach for reducing the risk of esophageal cancer in high-risk individuals (6).
Purpose: This study evaluated the effects of black raspberries (BRBs) on biomarkers of tumor development in the human colon and rectum including methylation of relevant tumor suppressor genes, cell proliferation, apoptosis, angiogenesis, and expression of Wnt pathway genes.Experimental Design: Biopsies of adjacent normal tissues and colorectal adenocarcinomas were taken from 20 patients before and after oral consumption of BRB powder (60 g/d) for 1-9 weeks. Methylation status of promoter regions of five tumor suppressor genes was quantified. Protein expression of DNA methyltransferase 1 (DNMT1) and genes associated with cell proliferation, apoptosis, angiogenesis, and Wnt signaling were measured.Results: The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1-9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction.Conclusions: These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted.
Our laboratory is developing a food-based approach to the prevention of esophageal and colon cancer utilizing freeze-dried berries and berry extracts. Dietary freeze-dried berries were shown to inhibit chemically-induced cancer of the rodent esophagus by 30-60% and of the colon by up-to 80%. The berries are effective at both the initiation and promotion/progression stages of tumor development. Berries inhibit tumor initiation events by influencing carcinogen metabolism, resulting in reduced levels of carcinogen-induced DNA damage. They inhibit promotion/progression events by reducing the growth rate of premalignant cells, promoting apoptosis, reducing parameters of tissue inflammation and inhibiting angiogenesis. On a molecular level, berries modulate the expression of genes involved with proliferation, apoptosis, inflammation and angiogenesis. We have recently initiated clinical trials; results from a toxicity study indicated that freeze-dried black raspberries are well tolerated in humans when administered orally for 7 days at a dose of 45 grams per day. Several Phase IIa clinical trials are underway in patients at high risk for esophagus and colon cancer; i.e., Barrett's esophagus, esophageal dysplasia and colonic polyps, to determine if berries will modulate various histological and molecular biomarkers of development of these diseases.
Diets containing either freeze-dried black raspberries (BRB) or their polyphenolic anthocyanins (AC) have been shown to inhibit the development of N- nitrosomethylbenzylamine (NMBA)-induced esophageal cancer in rats. The present study was conducted to determine if PCA, a major microbial metabolite of BRB AC, also prevents NMBA-induced esophageal cancer in rats. F344 rats were injected with NMBA three times a week (wk) for five weeks (wks) and then fed control or experimental diets containing 6.1% BRB, an AC-rich fraction derived from BRB, or PCA. Animals were exsanguinated at wks 15, 25, and 35 to quantify the development of preneoplastic lesions and tumors in the esophagus, and to relate this to the expression of inflammatory biomarkers. At wks 15 and 25, all experimental diets were equally effective in reducing NMBA-induced esophageal tumorigenesis, as well as in reducing the expression of Pentraxin-3 (PTX3), a cytokine produced by peripheral blood mononuclear cells in response to IL-1β and TNF-α. All experimental diets were also active at reducing tumorigenesis at wk 35; however, the BRB diet was significantly more effective than the AC and PCA diets. Further, all experimental diets inhibited inflammation in the esophagus via reducing biomarker (COX-2, iNOS, p-NF-κB, sEH) and cytokine (PTX3) expression. Overall, our data suggest that BRB, their component AC and PCA inhibit NMBA-induced esophageal tumorigenesis, at least in part, by their inhibitory effects on genes associated with inflammation.
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