Exp Biol Med (Maywood). 2004 Mar;229(3):255-63.
Pentameric procyanidins isolated from Theobroma cacao seeds selectively downregulate ErbB2 in human aortic endothelial cells.
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Kenny TP,
Keen CL,
Jones P,
Kung HJ,
Schmitz HH,
Gershwin ME.
Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, California 95616, USA.
Flavonoids isolated from cocoa have biological activities relevant to oxidant defenses, vascular health, tumor suppression, and immune function. The intake of certain dietary flavonoids, along with other dietary substances such as tocopherols, ascorbate, and carotenoids, is epidemiologically associated with a reduced risk of cardiovascular disease. Flavonoids have also been shown to modulate tumor pathology in vitro and in animal models. We took advantage of the conserved sequences found in tyrosine kinases to study the influence of cocoa fractions and controls on gene expression.
We report that the pentameric procyanidin (molecular weight of 1442 daltons) fraction isolated from cocoa was a potent inhibitor of tyrosine kinase ErbB2 expression, a receptor important in angiogenesis regulation. Consistent with this primary observation, the cocoa flavonoid fraction also suppressed human aortic endothelial cell (HAEC) growth and decreased expression of two tyrosine kinases responsive to ErbB2 modulation, namely VEGFR-2/KDR and MapK 11/p38beta2. These inhibitory effects were observed when HAECs were treated with the flavonol fraction (molecular weight 280 daltons) isolated from cocoa, which comprise the structural subunits from which the procyanidin flavonoid subclass is biosynthetically constructed. Down-regulation of ErbB2 and inhibition of HAEC growth by cocoa procyanidins may have several downstream implications, including
reduced vascular endothelial growth factor (VEGF) activity and angiogenic activity associated with tumor pathology. These results suggest specific dietary flavonoids are capable of selectively inhibiting ErbB2 and therefore may offer important insight into the design of therapeutic agents that target tumors overexpressing ErbB2.
PMID: 14988518 [PubMed - indexed for MEDLINE]
Mol Cancer Ther. 2005 Apr;4(4):537-46.
Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells.
Ramljak D,
Romanczyk LJ,
Metheny-Barlow LJ,
Thompson N,
Knezevic V,
Galperin M,
Ramesh A,
Dickson RB.
Department of Oncology, The Research Building, Room W417, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, District of Columbia 20057, USA.
A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G0/G1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that
pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo(a)pyrene-immortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G1-modulatory proteins: Cdc2 (at Tyr15), forkhead transcription factor (at Ser256, the Akt phosphorylation site) and p53 (Ser392). Dephosphorylation of p53 (at Ser392) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle regulatory proteins.
PMID: 15827326 [PubMed - indexed for MEDLINE]
J Am Coll Nutr. 2001 Oct;20(5 Suppl):436S-439S; discussion 440S-442S.
Chocolate: food as medicine/medicine as food.
Keen CL.
Department of Nutrition, University of California at Davis, 95616, USA.
clkeen@ucdavis.edu
Cocoa and chocolate products have been delicacies for hundreds of years. Only recently have they been recognized as significant sources of phytochemicals with healthful effects. These foods are among the most concentrated sources of the procyanidin flavonoids, catechin and epicatechin. Recent studies have shown that these polyphenols are absorbed from the intestine of animals and humans with epicatechin absorbed much more than catechin. These flavonoids have potent antioxidant and antiplatelet activities following consumption of cocoa or chocolate.
PMID: 11603654 [PubMed - indexed for MEDLINE]
Nutr Cancer. 2009;61(5):573-9.
Cancer protective properties of cocoa: a review of the epidemiologic evidence.
Maskarinec G.
Cancer Research Center of Hawaii, Honolulu, Hawaii, USA.
gertraud@crch.hawaii.edu
Due to their high concentration of catechins and procyanidins, bioactive compounds with distinct properties, cocoa and chocolate products may have beneficial health effects against oxidative stress and chronic inflammation, risk factors for cancer and other chronic diseases. This review focuses on the epidemiologic evidence for protective effects against cancer and overall mortality. The very small number of observational epidemiologic studies offers weak support for a reduction in mortality and little data related to cancer, whereas several intervention studies, despite their short duration, have reported some favorable changes in biomarkers assessing antioxidant status but very few findings related to inflammatory markers. In moderation, cocoa products may offer strong antioxidant effects in combination with a pleasurable eating experience. The benign profile of its fatty acids in combination with the low content of sugar of dark chocolate should lessen concerns about the adverse effects of cocoa products. Future nutritional trials need to assess a larger number of biomarkers that may be relevant for cancer risk, whereas epidemiologic studies require valid dietary assessment methods to examine the association of cocoa products with cancer risk in larger populations and to distinguish possible cancer protective effects of cocoa products from those due to other polyphenolic compounds.
PMID: 19838930 [PubMed - indexed for MEDLINE]
Cancer Lett. 2002 Jan 25;175(2):147-55.
Flavanols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells.
Carnésecchi S,
Schneider Y,
Lazarus SA,
Coehlo D,
Gossé F,
Raul F.
Laboratory of Nutritional Chemoprevention in Digestive Oncology, IRCAD, 1 place de l'hôpital, 67091, Strasbourg, France.
The effects of cocoa powder and extracts with different amounts of flavanols and related procyanidin oligomers were investigated on the growth of Caco-2 cells. Treatment of the cells with 50 microg/ml of procyanidin-enriched (PE) extracts caused a 70% growth inhibition with a blockade of the cell cycle at the G2/M phase. PE extracts caused a significant decrease of ornithine decarboxylase and S-adenosylmethionine decarboxylase activities, two key enzymes of polyamine biosynthesis. This led to a decrease in the intracellular pool of the polyamines. These
observations indicate that polyamine metabolism might be an important target in the anti-proliferative effects of cocoa polyphenols.
PMID: 11741742 [PubMed - indexed for MEDLINE]
Eur J Cancer Prev. 2006 Aug;15(4):353-61.
In-vitro effects of polyphenols from cocoa and beta-sitosterol on the growth of human prostate cancer and normal cells.
Jourdain C,
Tenca G,
Deguercy A,
Troplin P,
Poelman D.
BIOAlternatives, Gençay, France.
cjo@bioalternatives.com
Abstract
Cocoa contains many different types of physiologically active components. It was shown that cocoa beans are rich in specific antioxidants such as flavonoids, catechins, epicatechins and proanthocyanidins. Additionally, beta-sitosterol, the most common phytosterol, may play a protective role in the development of cancer. The aim of this in-vitro study was to evaluate the inhibitory effect of different cocoa polyphenols extracts, alone or combined with beta-sitosterol, on two human prostate cancer cell lines (nonmetastatic 22Rv1 cells and metastatic DU145 cells) and a normal human prostate cell line (RWEP-1). A synergy between beta-sitosterol and cocoa polyphenols extract was also researched. Cells were treated independently with five products from 1 to 72 h: (1/) synthetic beta-sitosterol, (2/) a cocoa polyphenols extract supplemented with beta-sitosterol, (3/) three different cocoa polyphenols extracts naturally containing beta-sitosterol. In the experiment, beta-sitosterol was tested from 10(-6) to 10(-3)%; cocoa polyphenols extract supplementation was with 0.72% beta-sitosterol; finally
cocoa polyphenols extracts were added to the cells at very low concentrations ranging from 0.001 to 0.2%. The growth and viability of cells were measured using colorimetric assay at 1, 3, 6, 24, 48 and 72 h of treatment. IC50 and IC100 corresponding to the concentration leading to a decrease of 50% and 100% of cell growth were determined.
At the highest tested concentration, cocoa polyphenols extracts induced a complete inhibition of growth of metastatic and nonmetastatic cancer cell lines. In addition, cocoa polyphenols extracts were more active against local cancer cells than against metastatic cells. Moreover, at the highest tested concentration, cocoa polyphenols extracts are not effective on a normal prostate cell lines. Beta-sitosterol induced low growth inhibition of both cancer cell line. Cocoa polyphenols extracts, however, were significantly more active and showed a strong and fast inhibition of cell growth than beta-sitosterol alone. No synergy or addition was observed when beta-sitosterol was tested together with the cocoa polyphenols extract. Our results show that cocoa polyphenols extracts have an antiproliferative effect on prostate cancer cell growth but not on normal cells, at the highest tested concentration.
PMID: 16835506 [PubMed - indexed for MEDLINE]
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