Although mortality rates from colorectal cancer have declined in both men and women over the past two decades, the 5-year survival from this disease is 64% and continues to decline to 57% at 10 years after diagnosis. For persons with distant metastases at diagnosis, the 5-year survival is only 10%. Therefore, the prevention of colon cancer remains an important goal and chemoprevention is a viable approach to achieve this goal. Our laboratory has been evaluating the use of freeze-dried berries, mainly black raspberries (BRBs), for the prevention of colon cancer in animals and in humans. The addition of BRB powder to the diet inhibited the development of colonic adenomas and carcinomas in azoxymethane (AOM)-treated rats, and of spontaneous adenomas in the intestine of ApcMin/+ mice. Two pilot intervention trials have been conducted in humans: one in patients with sporadic colorectal cancer and the other in patients with familial adenomatous polyposis (FAP). Our results suggest that short-term treatment of sporadic colorectal cancer patients with oral BRB powder (20g/3x/day) significantly reduced cell proliferation rates and produced a positive trend for changes in apoptosis, angiogenesis, and in genes associated with the Wnt pathway in colorectal tumors. Our FAP trial indicated that nine month treatment of FAP patients with BRB powder administered both orally (20g/3x/day) and in the form of rectal suppositories caused a 53% regression rate of rectal polyps. These results suggest that berries have potential for prevention of colorectal cancer in humans. Using bio-directed fractionation, we and our collaborators found that the anthocyanins in BRBs are important for their chemopreventive effects. Recent preliminary studies suggest that the colorectal cancer inhibitory effect of BRBs may be due, at least in part, to their ability to inhibit DNA methyltransferase 1 (DNMT1) protein expression and total DNMT activity in human colon tumor cells, which led to demethylation and reactivation of hypermethylation-silenced tumor suppressor genes such as p16. Short-term BRB intervention in colorectal cancer patients resulted in the demethylation of p16 and re-expression of the gene in aberrant crypts of colonic tumor tissues. We propose therefore to determine if demethylation and reactivation of hypermethylation- silenced genes by BRB anthocyanins in human colon cancer cells and in ApcMin/+ mice is associated with inhibition of tumorigenesis (Specific Aim 1) and the role of DNMT1 in BRB anthocyanin-induced demethylation of tumor suppressor genes (Specific Aim 2). We will also determine if BRBs influence the methylation state of hypermethylation-silenced tumor suppressor genes in specimens obtained from the two human BRB intervention trials, and its association with reduced cell proliferation and polyp regression (Specific Aim 3). Finally, we will conduct a pharmacokinetic study to determine the uptake of anthocyanins into human colon cells, and intestinal tissue and serum, as well as urinary levels of anthocyanins and their metabolites when administered at different concentrations in the diet to ApcMin/+ mice (Specific Aim 4). Ultimately, we plan to evaluate anthocyanins for prevention of colorectal cancer in humans.

Public Health Relevance

Colon cancer is the third most prevalent cancer, and the third leading cause of cancer death in the United States. Our laboratory is developing strategies for the prevention of colon cancer using freeze-dried berries. We now propose to evaluate the anthocyanins in berries for their ability to demethylate and reactivate tumor suppressor genes in colon cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemo/Dietary Prevention Study Section (CDP)
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Seifried, Harold E
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Medical College of Wisconsin
Internal Medicine/Medicine
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United States
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Pan, Pan; Oshima, Kiyoko; Huang, Yi-Wen et al. (2018) Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. Int J Cancer 143:886-896
Pan, Pan; Yu, Jianhua; Wang, Li-Shu (2018) Colon Cancer: What We Eat. Surg Oncol Clin N Am 27:243-267
Pan, Pan; Huang, Yi-Wen; Oshima, Kiyoko et al. (2018) An immunological perspective for preventing cancer with berries. J Berry Res 8:163-175
Pan, Pan; Peiffer, Daniel S; Huang, Yi-Wen et al. (2018) Inhibition of the development of N-nitrosomethylbenzylamine-induced esophageal tumors in rats by strawberries and aspirin, alone and in combination. J Berry Res 8:137-146
Pan, Pan; Skaer, Chad W; Wang, Hsin-Tzu et al. (2017) Systemic Metabolite Changes in Wild-type C57BL/6 Mice Fed Black Raspberries. Nutr Cancer 69:299-306
Pan, Pan; Lam, Vy; Salzman, Nita et al. (2017) Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats. Nutr Cancer 69:943-951
Pan, Pan; Kang, Siwen; Wang, Youwei et al. (2017) Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer. Front Immunol 8:997
Pan, Pan; Skaer, Chad; Yu, Jianhua et al. (2017) Berries and other natural products in the pancreatic cancer chemoprevention in human clinical trials. J Berry Res 7:147-161
Zhang, Wei; Chen, Jo-Hsin; Aguilera-Barrantes, Irene et al. (2016) Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-?-dependent gene expression. Mol Nutr Food Res 60:2387-2395
Peiffer, Daniel S; Wang, Li-Shu; Zimmerman, Noah P et al. (2016) Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer. Cancer Immunol Res 4:72-82

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