Effect of cyanidin‐3‐glucoside and an anthocyanin mixture from bilberry on adenoma development in the Apc^Min mouse model of intestinal carcinogenesis—Relationship with tissue anthocyanin levels

Abstract

Anthocyanins are dietary flavonoids, which can prevent carcinogen-induced colorectal cancer in rats. Here, the hypotheses were tested that Mirtoselect, an anthocyanin mixture from bilberry, or isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, interfere with intestinal adenoma formation in the Apc Min mouse, a genetic model of human familial adenomatous polyposis, and that consumption of C3G or Mirtoselect generates measurable levels of anthocyanins in the murine biophase. Apc Min mice ingested C3G or Mirtoselect at 0.03, 0.1 or 0.3% in the diet for 12 weeks, and intestinal adenomas were counted. Plasma, urine and intestinal mucosa were analyzed for presence of anthocyanins by high-pressure liquid chromatography with detection by UV spectrophotometry (520 nm) or tandem mass spectrometry (multiple reaction monitoring). Ingestion of either C3G or Mirtoselect reduced adenoma load dose-dependently. At the highest doses of C3G and Mirtoselect adenoma numbers were decreased by 45% (p < 0.001) or 30% (p < 0.05), respectively, compared to controls. Anthocyanins were found at the analytical detection limit in the plasma and at quantifiable levels in the intestinal mucosa and urine. Anthocyanin glucuronide and methyl metabolites were identified in intestine and urine. Total anthocyanin levels in mice on C3G or Mirtoselect were 43 ng and 8.1 lg/g tissue, respectively, in the intestinal mucosa, and 7.2 and 12.3 lg/ml in the urine. The efficacy of C3G and Mirtoselect in the Apc Min mouse renders the further development of anthocyanins as potential human colorectal cancer chemopreventive agents worthwhile. ' 2006 Wiley-Liss, Inc. Key words: colorectal cancer chemoprevention; anthocyanin; analysisThere is an increasing interest in the role of dietary constituents in the prevention of cancer. Examples of dietary components, which have been implicated as cancer chemopreventive agents, are flavonoids such as genistein from soya, quercetin from onions or apigenin from leafy vegetables.1 Dietary intake of these flavonoids is estimated to be within the range of 20-25 mg/day. Anthocyanins are flavonoids responsible for the bright blue and red colors of many fruits and berries. They are glycosides of anthocyanidins, mainly cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin, conjugated with sugars, including glucose, galactose and arabinose (for structures see Fig. 1). The daily intake of anthocyanins in the US is in excess of 200 mg/day, amounts far superior to those of genistein or quercetin.3 Anthocyanins and anthocyanidins have demonstrated antiproliferative activity in some cancer cell lines with IC 50 values for growth inhibition in the range of 100-800 and 18-200 lM, respectively.4,5 Anthocyanins-and anthocyanin-rich fruit extracts decreased aberrant crypt foci in rats exposed to azoxymethane 6 and reduced colonic adenocarcinoma burden in rats that had received azoxymethane, 1,2-dimethylhydrazine or 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine.6-8 The Apc Min (multiple intestin...

Dietary Cooked Navy Beans and Their Fractions Attenuate Colon Carcinogenesis in Azoxymethane-InducedOb/ObMice

“…These components include saponins (24)(25)(26); monosaccharides, disaccharides, and oligosaccharides (27); and the phenolic components ferulic acid (28,29), p-coumaric acid (30), kaempferol (31), phytate (32,33), and at smaller concentrations, catechins (34), anthocyanidins (35), and isoflavonoids (36). All of these components are primarily in aqueous-alcohol extracts of dry beans (37)(38)(39)(40).…”

Dietary Anthocyanins: Impact on Colorectal Cancer and Mechanisms of Action

“…In terms of absolute dose of agent, cyanidin-3-glucoside was less efficacious than the Mirtoselect mixture. Furthermore, authors suggested that different results obtained, in comparison with other studies (Kang et al, 2003) were possibly due in part to the higher dose of anthocyanins employed but also due to the different way of administration since anthocyanins tend to be unstable in aqueous solution at neutral pH (Cooke et al, 2006). Recently, bilberry [(BB),Vaccinium myrtillus], lingonberry (LB, Vaccinium vitis-idaea), and cloudberry (CB, Rubus chamaemorus), rich in anthocyanins, proanthocyanidins and ellagic acid respectively, proved to be chemopreventive as demonstrated by a significant reduction in the number of intestinal tumors in Min/1 mice.…”

Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention

“…Anthocyanin-rich berry extracts protected against esophageal cancer in rodents (6) and reduced adenoma development in Apc Min mice (7), a model of human familial adenomatous polyposis coli. Mirtocyan and cyanidin-3-glucoside as a single agent were also efficacious in the Apc Min model (8). Additionally, cyanidin-3-glucoside interfered with experimental skin tumorigenesis and reduced lung tumor growth and metastasis in the A549 nude mouse xenograft model (22).…”

“…18), which reduced adenoma number by 30% (8). The last third of the daily dose was administered in the early morning before surgery, when the patients were fasting.…”

“…Dietary phytochemicals exemplified by anthocyanins, bright blue-or red-colored polyphenols, which occur ubiquitously in vegetables and fruits, are attractive candidates for clinical evaluation, as they possess a good safety record. Studies in preclinical carcinogenesis models suggest that anthocyanins may prevent malignancies, notably in the gastrointestinal tract (3)(4)(5)(6)(7)(8). However, many aspects of their clinical pharmacology, such as concentrations achievable in organs targeted for prevention of malignancy, are only poorly understood.…”