Anthocyanins in Black Raspberries Prevent Esophageal Tumors in Rats

Abstract

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).

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

“…Their content in the powder was: cyanidin-3-glucoside (278.5 mg/100 g dry weight [DW]), cyanidin-3-sambubioside (56.0 mg/100 g DW), cyanidin-3-rutinoside (1,790 mg/100 g DW), and cyanidin-3-xylosylrutinoside (853.5 mg/100 g DW), resulting in a total anthocyanin content of 2,978 mg/100 g DW. We have shown previously that the anthocyanins in BRBs are chemopreventive in a rat model of esophageal cancer (22).…”

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

“…The evidence from a previous study shows that 5% whole freeze-dried black raspberries and the anthocyanin-rich fraction supplemented to N-nitrosomethylbenzylamine-induced F344 rats have chemopreventive potential, where the treatment groups inhibit cell proliferation, inflammation, angiogenesis, and induce apoptosis in both preneoplastic and papillomatous esophageal tissues [75]. Thus anthocyanins have chemoprophylaxis potential.…”

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer

“…Preclinical studies in our laboratory have shown that a chemopreventive approach using whole fruits and vegetables or their natural constituents has potential for prevention of esophageal SCC. Specifically, we have demonstrated the effectiveness of black raspberries (BRB) and their bioactive components in preventing the development of N-nitrosomethylbenzylamine (NMBA)-induced esophageal squamous cell papillomas in rats, some of which progress to carcinomas (3)(4)(5)(6).…”

“…The mechanisms by which BRBs and their component ACs impede tumorigenesis in the rat esophagus include reducing inflammation, cell proliferation, and angiogenesis, as well as stimulating apoptosis, cell differentiation, and cell adhesion (6). The inhibitory effects that BRBs and ACs have on inflammatory and angiogenic biomarkers in the esophagus are especially profound, including their ability to modulate the mRNA and protein expression of COX-2, inducible nitric oxide synthase (iNOS), NF-kB, IL1b, soluble epoxide hydrolase (sEH), pentraxin-3 (PTX3), CD34, VEGF, and HIFa (6)(7)(8)(9). BRB ACs are more effective at reducing inflammation than 5-aminosalicyclic acid, a common anti-inflammatory drug in vitro (10).…”

“…In addition, protocatechuic acid (PCA), a major microbial metabolite of BRB ACs (11,12), prevents NMBA-induced esophageal tumorigenesis, at least in part, by reducing biomarkers of inflammation and angiogenesis (13). In all studies to date, the reduction of inflammatory and angiogenic biomarkers by BRBs and their constituents correlated with reduced tumor multiplicity and burden in the NMBA-induced rat-esophageal cancer model (3,4,(6)(7)(8)(9)13).…”