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ABSTRACT: Oral consumption of freeze-dried black raspberries attenuated neoplastic changes in colorectal tissue markers of apoptosis, cell proliferation, and angiogenesis in colorectal cancer (CRC) patients. To determine whether plasma concentrations of interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, granulocyte macrophage colony stimulating factor (GM-CSF), interferon-γ, and tumor necrosis factor-α (TNF-α) were associated with berry treatment and changes in colorectal tissue markers of apoptosis, cell proliferation, and angiogenesis, plasma and biopsy samples of adenocarcinoma and adjacent normal-appearing colorectal tissue were collected before and during berry treatment from 24 CRC patients who had not received prior therapy and drank a slurry of black raspberry powder (20 g in 100 ml drinking water) 3 times a day for 1 to 9 wk. Plasma concentrations of GM-CSF (+0.12 ± 0.04 pg/mL; P = 0.01) and IL-8 (-1.61 ± 0.71 pg/mL; P = 0.04) changed in patients receiving berries for more than 10 days. These changes were correlated with beneficial changes in markers of proliferation (r(ΔGM-CSF, ΔKi67 carcinoma - normal) = -0.51) and apoptosis (r(ΔIL-8, ΔTUNEL carcinoma - normal) = -0.52) observed in colorectal tissue taken within the same week. Plasma concentrations of GM-CSF and IL-8 may serve as noninvasive indicators to monitor tissue response to berry-based interventions for CRC.
Nutrition and Cancer 07/2012; 64(6):820-5. · 2.78 Impact Factor
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Li-Shu Wang,
Mark Arnold,
Yi-Wen Huang, Christine Sardo,
Claire Seguin,
Edward Martin,
Tim H-M Huang,
Ken Riedl,
Steven Schwartz,
Wendy Frankel,
Dennis Pearl,
Yiqing Xu,
John Winston,
Guang-Yu Yang,
Gary Stoner
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ABSTRACT: This study evaluated the effects of black raspberries (BRBs) on biomarkers of tumor development in the human colon and rectum including methylation of relevant tumor suppressor genes, cell proliferation, apoptosis, angiogenesis, and expression of Wnt pathway genes.
Biopsies of adjacent normal tissues and colorectal adenocarcinomas were taken from 20 patients before and after oral consumption of BRB powder (60 g/d) for 1-9 weeks. Methylation status of promoter regions of five tumor suppressor genes was quantified. Protein expression of DNA methyltransferase 1 (DNMT1) and genes associated with cell proliferation, apoptosis, angiogenesis, and Wnt signaling were measured.
The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1-9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction.
These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted.
Clinical Cancer Research 02/2011; 17(3):598-610. · 7.74 Impact Factor
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ABSTRACT: Colorectal cancer (CRC) is the leading digestive tract cancer in the Western world, particularly in the United States where
it accounts for approximately 10% of all cancer deaths. The multistage development of CRC is associated with chromosomal instability,
DNA-repair defects, aberrant DNA methylation, and mutational events in oncogenes and tumor suppressor genes. Preclinical studies
using cultured human colon tumor cells and animal models of colorectal cancer indicate that black raspberries (BRBs) and their
constituent anthocyanins and ellagitannins elicit chemopreventive effects against CRC. A 7-day Phase I trial indicated that
BRBs are well tolerated by humans and their component anthocyanins and ellagic acid are absorbed into blood. The results of
a Phase Ib trial in which BRBs were administered daily to colorectal cancer patients from the time of diagnosis of the disease
until surgical removal of the tumor (average = 3 weeks) are presented in this chapter. BRB treatment resulted in reduced proliferation
and increased apoptosis of CRC cells. In addition, tumor angiogenesis was inhibited by berries. BRB treatment reduced ß-catenin
expression and enhanced E-cadherin expression in CRC indicating a protective effect on the Wnt signaling pathway. DNA methylation
assays showed that BRBs are capable of demethylating tumor suppressor genes associated with the Wnt pathway, in part, through
inhibiting the expression of DNMT1, a DNA methyltransferase that is commonly overexpressed in CRC. These data suggest that
BRBs should be further examined for chemopreventive effects against CRC.
KeywordsChemoprevention-Human-Colon-Cancer-Black raspberries-DNA methylation-Proliferation-Apoptosis-Angiogenesis
12/2010: pages 281-303;
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ABSTRACT: 1. Berries have been part of the human diet for many centuries. They are a rich source of known chemopreventive agents including
provitamin A carotenoids, C, E, and folate, calcium and selenium, simple and complex phenols, and phytosterols.
2. It has been found that freeze-dried berries can inhibit cancer development in the esophagus, colon, oral cavity, and mammary
gland of rodents. Studies suggest that the most active inhibitory compounds in berries are the anthocyanins, the most abundant
flavonoids in berries.
3. Berries function to inhibit carcinogenesis by reducing the growth rate of premalignant cells, inhibiting angiogenesis and
inflammation, and stimulating apoptosis, cell differentiation, and cell adhesion. Molecular studies indicate that berries
exhibit a genome-wide effect on the expression of genes associated with these different cellular functions.
4. The ability of berries to prevent cancer is likely due to the localized absorption of berry compounds into target tissues.
Topical treatment of oral dysplastic lesions with a black raspberry gel for a period of 6 weeks resulted in a reduction in
histological grade and restoration of loss of heterozygosity (LOH) in about 50% of the lesions. Consumption of black raspberry
powder (60g/day) in a slurry of water for only 2–4 weeks reduced the Ki-67 cell proliferation index in colon tumors taken
at surgery from cancer patients.
5. The protective effects of berries on cancer development at specific sites in animals are impressive; however, there is
little evidence that berry consumption leads to significant side effects either in animals or in humans. It seems reasonable
to suggest that berries be part of the daily diet, and that in individuals at high risk, the daily consumption of several
grams of berry powder could well elicit protection.
Key WordsBerries-cancer chemoprevention-anthocyanins-esophagus-colon-oral cavity-molecular mechanisms
12/2009: pages 703-723;
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ABSTRACT: Our laboratory is developing a food-based approach to the prevention of esophageal and colon cancer utilizing freeze-dried berries and berry extracts. Dietary freeze-dried berries were shown to inhibit chemically induced cancer of the rodent esophagus by 30-60% and of the colon by up to 80%. The berries are effective at both the initiation and promotion/progression stages of tumor development. Berries inhibit tumor initiation events by influencing carcinogen metabolism, resulting in reduced levels of carcinogen-induced DNA damage. They inhibit promotion/progression events by reducing the growth rate of pre-malignant cells, promoting apoptosis, reducing parameters of tissue inflammation and inhibiting angiogenesis. On a molecular level, berries modulate the expression of genes involved with proliferation, apoptosis, inflammation and angiogenesis. We have recently initiated clinical trials; results from a toxicity study indicated that freeze-dried black raspberries are well tolerated in humans when administered orally for 7 days at a dose of 45 g per day. Several Phase IIa clinical trials are underway in patients at high risk for esophagus and colon cancer; i.e., Barrett's esophagus, esophageal dysplasia and colonic polyps, to determine if berries will modulate various histological and molecular biomarkers of development of these diseases.
Seminars in Cancer Biology 11/2007; 17(5):403-10. · 6.47 Impact Factor
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Gary D Stoner, Christine Sardo,
Glen Apseloff,
Dan Mullet,
Wayne Wargo,
Vickie Pound,
Alpana Singh,
James Sanders,
Robeena Aziz,
Bruce Casto,
XiaoLi Sun
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ABSTRACT: Eleven subjects completed a clinical trial to determine the safety/tolerability of freeze-dried black raspberries (BRB) and to measure, in plasma and urine, specific anthocyanins-cyanidin-3-glucoside, cyanidin-3-sambubioside, cyanidin-3-rutinoside, and cyanidin-3-xylosylrutinoside, as well as ellagic acid. Subjects were fed 45 g of freeze-dried BRB daily for 7 days. Blood samples were collected predose on days 1 and 7 and at 10 time points postdose. Urine was collected for 12 hours predose on days 1 and 7 and at three 4-hour intervals postdose. Maximum concentrations of anthocyanins and ellagic acid in plasma occurred at 1 to 2 hours, and maximum quantities in urine appeared from 0 to 4 hours. Overall, less than 1% of these compounds were absorbed and excreted in urine. None of the pharmacokinetic parameters changed significantly between days 1 and 7. In conclusion, 45 g of freeze-dried BRB daily are well tolerated and result in quantifiable anthocyanins and ellagic acid in plasma and urine.
The Journal of Clinical Pharmacology 11/2005; 45(10):1153-64. · 2.91 Impact Factor
