Article

Protection against esophageal cancer in rodents with lyophilized berries: potential mechanisms. Nutr Cancer

Division of Hematology and Oncology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus 43210, USA.
Nutrition and Cancer (Impact Factor: 2.47). 02/2006; 54(1):33-46. DOI: 10.1207/s15327914nc5401_5
Source: PubMed

ABSTRACT For several years, our laboratory has been evaluating the ability of lyophilized (freeze-dried) black raspberries (Rubus occidentalis, BRBs), blackberries (R. fructicosus, BBs), and strawberries (Fragaria ananasia, STRWs) to inhibit carcinogen-induced cancer in the rodent esophagus. To assure "standardized" berry preparations for study, each berry type is of the same cultivar, picked at about the same degree of ripeness, washed and frozen within 2-4 h of the time of picking, and freeze-dried under conditions that preserve the components in the berries. Some of the known chemopreventive agents in berries include vitamins A, C, and E and folic acid; calcium and selenium; beta-carotene, alpha-carotene, and lutein; polyphenols such as ellagic acid, ferulic acid, p-coumaric acid, quercetin, and several anthocyanins; and phytosterols such as beta-sitosterol, stigmasterol, and kaempferol. In initial bioassays, freeze-dried STRW, BRB, and BB powders were mixed into AIN-76A synthetic diet at concentrations of 5% and 10% and fed to Fischer 344 rats before, during, and after treatment with the esophageal carcinogen N-nitrosomethylbenzylamine (NMBA). At 25 wk of the bioassay, all three berry types were found to inhibit the number of esophageal tumors (papillomas) in NMBA-treated animals by 24-56% relative to NMBA controls. This inhibition correlated with reductions in the formation of the NMBA-induced O6-methylguanine adduct in esophageal DNA, suggesting that the berries influenced the metabolism of NMBA leading to reduced DNA damage. Studies are ongoing to determine the mechanisms by which berries influence NMBA metabolism and DNA adduct formation. BRBs and STRWs were also tested in a postinitiation scheme and were found to inhibit NMBA-induced esophageal tumorigenesis by 31-64% when administered in the diet following treatment of the animals with NMBA. Berries, therefore, inhibit tumor promotion and progression events as well as tumor initiation. In vivo mechanistic studies with BRBs indicate that they reduce the growth rate of premalignant esophageal cells, in part, through down-regulation of cyclooxygenase-2 leading to reduced prostaglandin production and of inducible nitric oxide synthase leading to reduced nitrate/nitrite levels in the esophagus. Based upon the preclinical data on rodents, we have initiated prevention trials in humans to determine if berries might exhibit chemopreventive effects in the esophagus.

Download full-text

Full-text

Available from: Gary D Stoner, May 08, 2014
0 Followers
 · 
116 Views
  • Source
    • "These intriguing data, though limited, warrant further investigation of freeze-dried strawberry supplementation in animal models of other common forms of gastrointestinal malignancies, such as colon and gastric cancer. Data further suggest a synergistic effect among phytochemicals and micronutrients in strawberries in exerting protection against carcinogenesis (Stoner et al., 2006, 2010). "
    [Show abstract] [Hide abstract]
    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 · 5.55 Impact Factor
  • Source
    • "Dietary anthocyanins exercise their main anticancer effects in the gastrointestinal tract, because they can reach relatively high concentrations in direct contact with the mucosa (He and others 2005), for example, black raspberries prevented the development of esophageal tumors in rats treated with carcinogen (N-nitrosomethylbenzylamine; see other example at Table 5). Anthocyanins may act by inhibiting the mRNA and protein expression levels of COX-2, inducible nitric oxide synthetase (iNOS), VEGF, and other genes associated with cell proliferation, inflammation, and angiogenesis (Stoner and others 2006). They also appear to be active against colon cancer, which develops through local irritation, producing a local inflammatory response and through an imbalance of electrolytes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anthocyanins belong to the flavonoid group of polyphenolic compounds, which are responsible for the red and blue colors of plant organs such as fruits, flowers, and leaves. Due to their frequent presence in plants, particularly berry fruits, vegetables, and grapes, they are key components of the human diet. Interest in anthocyanins has increased widely during the past decade. Numerous studies have suggested that anthocyanins have a wide range of health-promoting properties. These compounds are therefore considered to be a functional food factor, which may have important implications in the prevention of chronic diseases. The aim of this body of work is to investigate and review the current literature on anthocyanins, and particularly their pharmacokinetics and any health-promoting properties, in order to summarize existing knowledge and highlight any aspects that require further study and analysis.
    Comprehensive Reviews in Food Science and Food Safety 09/2013; 12(5). DOI:10.1111/1541-4337.12024 · 3.54 Impact Factor
  • Source
    • "Histopathology of NMBA-induced lesions in rat esophagus (from Stoner et al., 2006 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.
    Toxicology and Applied Pharmacology 12/2007; 224(3):337-49. DOI:10.1016/j.taap.2007.01.030 · 3.63 Impact Factor
Show more