Anthocyanins are the most abundant flavonoid constituents of fruits and vegetables. The conjugated bonds in their structures, which absorb light at about 500 nm, are the basis for the bright red, blue and purple colors of fruits and vegetables, as well as the autumn foliage of deciduous trees. The daily intake of anthocyanins in residents of the United States is estimated to be about 200 mg or about 9-fold higher than that of other dietary flavonoids. In this review, we summarize the latest developments on the anti-carcinogenic activities of anthocyanins and anthocyanin-rich extracts in cell culture models and in animal model tumor systems, and discuss their molecular mechanisms of action. We also suggest reasons for the apparent lack of correlation between the effectiveness of anthocyanins in laboratory model systems and in humans as evidenced by epidemiological studies. Future studies aimed at enhancing the absorption of anthocyanins and/or their metabolites are likely to be necessary for their ultimate use for chemoprevention of human cancer.

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This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action.Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase I1 (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation-and TPA-induced epidermal ornithine decarboxylase ( O X ) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication.Curcumin is the yellow coloring agent in the spice turmeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts.Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin. Ellagic acid functions through a variety of mechanisms, including inhibition of microsomal P-450 enzymes, stimulation of glutathione-S-transferase, scavenging the reactive metabolites of carcinogens, and direct binding to DNA, thus potentially masking sites that would...

Squamous cell carcinoma (SCC) of the human esophagus has a multifactorial etiology involving several environmental and/or genetic factors. Current modalities of therapy for this disease offer poor survival and cure rates. Although a number of approaches could be undertaken to reduce the occurrence of esophageal SCC, including changes in lifestyle and improved nutrition, such approaches are not easily implemented. Chemoprevention offers a viable alternative that is likely to be effective against this disease. Clinical investigations in areas of high incidence of esophageal SCC have shown that primary chemoprevention of this disease is feasible, if potent inhibitors are identified. Studies in the Fischer 344 rat model of nitrosamine-induced tumorigenesis have proven valuable in understanding the biology of esophageal SCCs and help identify surrogate end-point biomarkers and putative agents that can be useful in human chemoprevention studies. Several compounds that inhibit tumor initiation by suspected human esophageal carcinogens have been identified using this model. These include diallyl sulfide, isothiocyanates and several polyphenolic compounds. Novel biomarkers, including nuclear/nucleolar morphometry using computer-assisted image analysis of preneoplastic lesions, have been developed to measure efficacy of chemopreventive agents against esophageal SCC. The identification of single agents that inhibit the progression of dysplastic lesions, however, has proven difficult. Results from a food-based approach suggest that the use of freeze-dried berry preparations can affect both initiation and promotion/progression of esophageal SCC in an animal model. These observations provide valuable information for future studies on chemoprevention of cancers of the esophagus in a clinical setting. Given the complex etiology of esophageal SCC, it is felt that the most effective chemoprevention strategies would include agents that reduce mutational events associated with carcinogen exposure in combination with agents that inhibit the progression of intraepithelial dysplasia to invasive cancer.

The strain A mouse has a high incidence of spontaneous lung tumors and is susceptible to lung tumor induction by chemical carcinogens. By utilizing transfection assay, Southern blot analysis, and DNA amplification techniques, we have detected an activated Ki-ras gene in the DNAs of both spontaneously occurring and chemically induced lung tumors of strain A mice. The point mutations in the spontaneous lung tumors were in both codon 12 (60%) and codon 61 (30%). In contrast, 100% of the mutations in the Ki-ras gene detected in methylnitrosourea-induced lung tumors and 93% of the mutations in the Ki-ras genes detected in benzo[ajpyreneinduced lung tumors were in codon 12, whereas 90% of the mutations in the Ki-ras genes detected in ethyl carbamateinduced lung tumors were in codon 61. The selectivity of mutations in the Ki-ras oncogene observed in chemically induced tumors, as compared to spontaneous tumors, suggests that these chemicals directly induce point mutations in the Ki-ras protooncogene. These data indicate that the strain A mouse lung tumor model is a very sensitive system to detect the ability of chemicals to activate the Ki-ras protooncogene in lung tissue.The strain A mouse lung tumor bioassay has been utilized for testing more than 300 compounds for carcinogenic activity (1-4). The strain A mouse also has a very high incidence of spontaneous lung tumors (nearly 100%o by 2 years of age), which is often a complicating factor in interpreting bioassay test results for carcinogenicity (1-4). The detection and characterization of activated oncogenes involved in the development of both spontaneously occurring and chemically induced lung tumors ofthe strain A mouse may offer one approach to define the mechanism(s) by which a chemical causes an increased incidence of lung tumors. Activated ras oncogenes have been detected in spontaneously occurring and chemically induced liver tumors of the B6C3F1 mouse (5-8) and the pattern of activating mutations in these tumors has been compared. More than 60% of the activated oncogenes detected in furan-and furfural-associated liver tumors of the B6C3F1 mouse were different from those seen in spontaneous B6C3F1 mouse liver tumors. Activating mutations in the Ha-ras gene and several activated Ki-ras genes were detected in chemically induced mouse liver tumors, indicating that furan and furfural caused an increase in mouse liver tumors at least in part by a genotoxic mechanism (7). Likewise, Wiseman et al. (8) MATERIALS AND METHODS Rodent Tumors. Spontaneous lung tumors were obtained from untreated, 24-to 27-month-old strain A/HeN mice (National Institute of Aging, Bethesda, MD). Strain A/J mice (6-8 weeks old, The Jackson Laboratories) were administered B[a]P by oral intubation at 3 mg per dose, once a week, for 4 weeks (9). EC and MNU were administered i.p. in a single injection with a dose of either 1000 mg/kg of body weight (for EC) or 150 mg/kg of body weight (for MNU) (10). At 12 months, individual lung tumors were collected and quick frozen in liquid nitrogen...

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).

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