Multiple Berry Types Prevent N-nitrosomethylbenzylamine-Induced Esophageal Cancer in Rats

Department of Internal Medicine and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Pharmaceutical Research (Impact Factor: 3.42). 03/2010; 27(6):1138-45. DOI: 10.1007/s11095-010-0102-1
Source: PubMed


The present study compared the ability of different berry types to prevent chemically-induced tumorigenesis in the rat esophagus. We also determined if berries influence the levels of inflammatory cytokines in the serum of carcinogen-treated rats.
Rats were treated with the carcinogen N-nitrosomethylbenzylamine (NMBA) for 5 weeks, then placed on diets containing 5% of either black or red raspberries, strawberries, blueberries, noni, açaí or wolfberry until the end of the study. The effects of the berries on tumor incidence, multiplicity and size were determined, as well as their effects on the levels of selected inflammatory cytokines in serum.
All berry types were about equally effective in inhibiting NMBA-induced tumorigenesis in the rat esophagus. They also reduced the levels of the serum cytokines, interleukin 5 (IL-5) and GRO/KC, the rat homologue for human interleukin-8 (IL-8), and this was associated with increased serum antioxidant capacity.
Seven berry types were about equally capable of inhibiting tumor progression in the rat esophagus in spite of known differences in levels of anthocyanins and ellagitannins. Serum levels of IL-5 and GRO/KC (IL-8) may be predictive of the inhibitory effect of chemopreventive agents on rat esophageal carcinogenesis.

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Available from: Gary D Stoner, May 08, 2014
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    • "Esophageal cancer chemoprevention studies have suggested that some natural foods, such as strawberries, blueberries, and black raspberries, and chemical monomers are associated with a reversal of esophageal dysplasia [7]. Recently, chemoprevention studies based on a phase II clinical trial in esophageal cancer showed that strawberries could significantly reduce the histological grade of precancerous lesions of the esophagus [8]. "
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    ABSTRACT: The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.
    PLoS ONE 09/2014; 9(9):e107204. DOI:10.1371/journal.pone.0107204 · 3.23 Impact Factor
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    • "28 μg/mL; implicated in prevention of colon carcinogenesis Stoner et al. (2010) "
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    ABSTRACT: Emerging research provides substantial evidence to classify strawberries as a functional food with several preventive and therapeutic health benefits. Strawberries, a rich source of phytochemicals (ellagic acid, anthocyanins, quercetin, and catechin) and vitamins (ascorbic acid and folic acid), have been highly ranked among dietary sources of polyphenols and antioxidant capacity. It should however be noted that these bioactive factors can be significantly affected by differences in strawberry cultivars, agricultural practices, storage, and processing methods: freezing versus dry heat has been associated with maximum retention of strawberry bioactives in several studies. Nutritional epidemiology shows inverse association between strawberry consumption and incidence of hypertension or serum C-reactive protein; controlled feeding studies have identified the ability of strawberries to attenuate high-fat diet induced postprandial oxidative stress and inflammation, or postprandial hyperglycemia, or hyperlipidemia in subjects with cardiovascular risk factors. Mechanistic studies have elucidated specific biochemical pathways that might confer these protective effects of strawberries: upregulation of endothelial nitric oxide synthase (eNOS) activity, downregulation of NF-kB activity and subsequent inflammation, or inhibitions of carbohydrate digestive enzymes. These health effects may be attributed to the synergistic effects of nutrients and phytochemicals in strawberries. Further studies are needed to define the optimal dose and duration of strawberry intake in affecting levels of biomarkers or pathways related to chronic diseases.
    Critical reviews in food science and nutrition 01/2014; 54(6):790-806. DOI:10.1080/10408398.2011.608174 · 5.18 Impact Factor
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    • "Given its benefits to human health, in order to extend the shelf life and preserve the pigment stability of açaí, which is otherwise a highly perishable fruit, a spray-drying technique can be used to produce açaí powder with high anthocyanin content (Tonon et al., 2010). Due to the increased popularity of açaí consumption (Vidigal et al., 2011; Menezes et al., 2011) and the lack of studies on its anti-tumor property in chemically induced rodent cancer models (Stoner et al., 2010; Fragoso et al., 2012), the present study was conducted to investigate the potential protective effect of spraydried açaí powder (AP) against rat colon carcinogenesis using ACF formation and tumor development as the end-points. "
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    ABSTRACT: This study investigated the protective effect of spray-dried açaí powder (AP) intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4 weeks of DMH administrations, the groups were fed with standard diet, a diet containing 2.5% or 5.0% AP or a diet containing 0.2% N-acetylcysteine (NAC) for 10 weeks, using aberrant crypt foci (ACF) as the endpoint. Additionally, two groups were fed with standard diet or a diet containing 5.0% AP for 20 weeks, using colon tumors as the endpoint. In ACF assay, a reduction in the number of aberrant crypts (AC) and ACF (1-3 AC) were observed in the groups fed with 5.0% AP (37% AC and 47% ACF inhibition, p= 0.036) and 0.2% NAC (39% AC and 41% ACF inhibition, p= 0.042). In tumor assay, a reduction in the number of invasive tumors (p< 0.005) and tumor multiplicity (p= 0.001) was observed in the group fed with 5.0% AP. Also, a reduction in tumor Ki-67 cell proliferation (p= 0.003) and net growth index (p= 0.001) was observed in the group fed with 5.0% AP. Therefore the findings of this study indicate that AP feeding may reduce the development of chemically-induced rat colon carcinogenesis.
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