Tart cherry anthocyanins inhibit tumor development in ApcMin mice and reduce proliferation of human colon cancer cells☆
Introduction
Tart cherries contain substantial quantities of anthocyanins in addition to other bioflavonoids [1]. Anthocyanins (Fig. 1), a member of the bioactive phytochemicals, are widely distributed in fruits, vegetables and beans, suggesting that plant-based diets can provide considerable amounts of anthocyanins [2], [3]. Like the vast majority of flavonoids, anthocyanins primarily occur in plants as glycosides. Cyanidin is the major anthocyanin aglycone in tart cherries. Montmorency and Balaton™ tart cherries contain 0.40–0.80 mg/g, respectively, of anthocyanins [1]. These anthocyanins were found to function as antioxidants and cyanidin was shown to inhibit the activities of cyclooxygenase (COX) enzymes in vitro [2], [4]. Several studies have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of colon tumors in animal models and reduce the risk of colon cancer in humans [5], [6]. In most cases, colon carcinogenesis depends on mutation of the adenomatous polyposis coli (APC) gene, which is considered a gatekeeper in the carcinogenic process [7]. Human APC gene germline mutations cause familial adenomatous polyposis, an autosomal dominantly inherited disease that predisposes affected individuals to develop numerous adenomatous polyps and, ultimately, colorectal cancer. APC gene mutations also are a frequent and early event in sporadic colon cancer. ApcMin mice are a mutant mouse lineage predisposed to multiple intestinal neoplasia (Min) due to a mutation in the murine homolog of the APC gene [8]. The primary phenotype of ApcMin mice is the development of multiple intestinal adenomas.
The objectives of this research were to determine the potential of tart cherry anthocyanins and cyanidin to inhibit intestinal tumor development in ApcMin mice and to determine the potential of anthocyanins and cyanidin to directly inhibit the growth of human colon cancer cells.
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Animals and diets
This research was conducted with approval of the Michigan State University All-University Committee on Animal Use and Care. ApcMin mice were produced by mating normal C57BL/6J (Apc+/+) female mice with Min C57BL/6J (ApcMin/+) male mice. ApcMin progeny were identified by a polymerase chain reaction (PCR)-based assay [8] and were randomly assigned to five treatment groups (n=10 per group; equal numbers of males and females) at 4–5 weeks of age and fed treatment diets for 10 weeks. The treatments
Results
Final body weights of mice were significantly influenced by treatment and averaged 22.8, 24.1, 21.3, 19.7, and 25.5 g for mice consuming control diet, anthocyanins, cyanidin, tart cherries, and sulindac, respectively. Final body weights for mice consuming anthocyanins and sulindac were greater (P<0.05) than for mice consuming tart cherries.
Treatments had differential effects on tumor incidence and burden in the various sections of the intestinal tract. Mice consuming anthocyanins, cyanidin, or
Discussion
Our interest in testing the potential of tart cherry anthocyanins and cyanidin to inhibit tumor development in ApcMin mice stemmed from the observation that these compounds inhibit the activities of COX enzymes [4]. Other studies have demonstrated that sulindac (and other NSAIDs) reduce small intestinal tumor multiplicity and size in ApcMin mice [10], [11], [12]. In this study, we found that anthocyanins, cyanidin, and tart cherries (presumably as a source of anthocyanins) all significantly
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Supported by USDA grant 99-35503-8147 (M.G.N., L.D.B.), the Michigan State University Project GREEEN Initiative, and the Cherry Marketing Institute.