Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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21:
Food Chem Toxicol. 2007
Feb;45(2):286-95. Epub 2006 Aug 30.
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The inhibition of human glutathione S-transferases
activity by plant polyphenolic compounds ellagic
acid and curcumin.
Hayeshi R,
Mutingwende I,
Mavengere W,
Masiyanise V,
Mukanganyama S.
Biomolecular Interactions Analyses Group, Department
of Biochemistry, University of Zimbabwe, P.O. Box MP
167, Mount Pleasant, Harare, Zimbabwe.
Glutathione S-transferases (GSTs) are
multifunctional detoxification proteins that protect
the cell from electrophilic compounds.
Overexpression of GSTs in cancer results in
resistance to chemotherapeutic agents and inhibition
of the over expressed GST has been suggested as an
approach to combat GST-induced resistance. The
inhibition of human recombinant GSTs by natural
plant products was investigated in this study. Using
1-chloro-2,4 dinitrobenzene (CDNB) as a substrate,
ellagic acid and curcumin were shown to inhibit GSTs
A1-1, A2-2, M1-1, M2-2 and P1-1 with IC(50) values
ranging from 0.04 to 5 microM whilst genistein,
kaempferol and quercetin inhibited GSTs M1-1 and
M2-2 only. The predominant mode of inhibition with
respect to the G and H-sites were mixed inhibition
and uncompetitive to a lesser extent. The K(i) (K(i)('))
values for ellagic acid and curcumin with respect to
GSH and CDNB were in the range 0.04-6 microM showing
the inhibitory potency of these polyphenolic
compounds. Ellagic acid and curcumin also showed
time- and concentration-dependent inactivation of
GSTs M1-1, M2-2 and P1-1 with curcumin being a more
potent inactivator than ellagic acid. These results
facilitate the understanding of the interaction of
human GSTs with plant polyphenolic compounds with
regards to their role as chemomodulators in cases of
GST-overexpression in malignancies.
Publication Types:
PMID: 17046132 [PubMed - indexed for MEDLINE]
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Site-specific accumulation of the cancer
preventive dietary polyphenol ellagic acid in
epithelial cells of the aerodigestive tract.
Whitley AC,
Sweet DH,
Walle T.
Department of Cell and Molecular Pharmacology and
Experimental Therapeutics, Medical University of
South Carolina, 173 Ashley Avenue, PO Box 250505,
Charleston, SC 29425, USA.
Ellagic acid (EA), a polyphenol present in berries,
has been demonstrated to prevent oesophageal and
colon cancer in animals. To better understand the
site-specificity of these effects, we studied the
accumulation and transport of [14C]EA in rat
aerodigestive epithelial cells in-vivo and in
cultured human cells. When [14C]EA was administered
to rats by gavage, a high content of EA was found in
the oesophagus and small intestine at 0.5 h after
oral administration and in the colon at 12 h, with
very low amounts in plasma and peripheral tissues.
Studies in human intestinal Caco-2 and human
oesophageal HET-1A cells found very limited
transcellular transport (Caco-2) of EA but high
accumulation (Caco-2 and HET-1A) in the cells. In
more detailed studies in the Caco-2 cells,
accumulation of EA displayed ATP- and
Na+-dependency. Multiple interventions permitted the
exclusion of a number of transporters as mediators
of this uptake. A dramatically reduced transport of
EA at low pH (5.5) compared with high pH (7.4)
suggested an important role for the negative charge
of EA. This was supported by the organic anion
transport inhibitors
4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid
and bromosulfophthalein. The latter produced as much
as 78% inhibition at the 100 microM concentration.
Finally, Caco-2 cells were shown to express organic
anion transporter 4 (OAT4) mRNA, as was the human
large intestine. EA appears to be accumulated along
the aerodigestive tract using OAT-like transporters,
one of which might be OAT4.
Publication Types:
PMID: 16945178 [PubMed - indexed for MEDLINE]
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Induction of cell death in Caco-2 human colon
carcinoma cells by ellagic acid rich fractions from
muscadine grapes (Vitis rotundifolia).
Mertens-Talcott SU,
Lee JH,
Percival SS,
Talcott ST.
Department of Pharmaceutics, University of Florida,
P. O. Box 110494, Gainesville, Florida 32610-0494,
USA.
Possible anticancer mechanisms exerted by
polyphenolic compounds contained in fruits and
vegetables include antioxidant activity, the
inhibition of proliferation, and the induction of
apoptosis in cancer cells. This study examined the
effects of four isolated polyphenolic extracts from
red muscadine grapes (Vitis rotundifolia) on vital
cell parameters and the induction of apoptosis in
Caco-2 colon carcinoma cells. The magnitude of
effects in cell culture was then correlated to
polyphenolic composition and antioxidant capacity.
Whereas anticancer effects of individual
polyphenolic compounds have been demonstrated
multiple times, information relating to anticancer
effects of polyphenolic extracts is not available in
abundance. All four extracts induced apoptosis,
decreased cell number, and caused alterations in
cell cycle kinetics in a concentration-dependent
manner. The efficacy of the polyphenolics on vital
cell parameters correlated well to the presence of
ellagic acid glycosides and flavonoids and also to
the antioxidant capacity. This study demonstrated
the anticancer properties of ellagic acid rich
extracts from red muscadine juice.
PMID: 16848514 [PubMed - indexed for MEDLINE]
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Ellagic acid and natural sources of ellagitannins
as possible chemopreventive agents against
intestinal tumorigenesis in the Min mouse.
Päivärinta E,
Pajari AM,
Törrönen R,
Mutanen M.
Department of Applied Chemistry and Microbiology,
University of Helsinki, Finland.
Ellagic acid has been shown to have chemopreventive
effects in various experimental cancer models. We
wanted to see whether pure ellagic acid and natural
ellagitannins from cloudberry (Rubus chamaemorus)
seed and pulp have any effect on adenoma formation
in Apc-mutated Min mice. From the age of 5 wk, the
mice were fed either a control diet, a diet
containing pure ellagic acid at 1,564 mg/kg, or
diets containing 4.7% (wt/wt) cloudberry seeds or
5.3% cloudberry pulp. The concentrations of
ellagitannins and free ellagic acid in the seed diet
were 807 and 42 mg/kg and in the pulp diet 820 and
34 mg/kg, respectively. After the 10-wk feeding
period, ellagic acid had no effect on the number or
size of adenomas in the distal or total small
intestine, but it increased adenoma size in the
duodenum when compared with the control diet
(1.50+/-0.29 vs. 1.16+/-0.31 mm; P=0.029). Neither
cloudberry seed nor pulp diets had any effect on the
adenoma formation. Chemopreventive effects and
mechanisms of whole cloudberry and other similar
sources of phenolic compounds should, however, be
studied, further taking into account food matrix and
interactions with other dietary constituents that
may be involved in the bioavailability and
metabolism of ellagitannins.
Publication Types:
PMID: 16800775 [PubMed - indexed for MEDLINE]
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Protection against esophageal cancer in rodents
with lyophilized berries: potential mechanisms.
Stoner GD,
Chen T,
Kresty LA,
Aziz RM,
Reinemann T,
Nines R.
Division of Hematology and Oncology, Department of
Internal Medicine, Ohio State University
Comprehensive Cancer Center, Columbus 43210, USA.
gary.stoner@osumc.edu
For several years, our laboratory has been
evaluating the ability of lyophilized (freeze-dried)
black raspberries (Rubus occidentalis, BRBs),
blackberries (R. fructicosus, BBs), and strawberries
(Fragaria ananasia, STRWs) to inhibit
carcinogen-induced cancer in the rodent esophagus.
To assure "standardized" berry preparations for
study, each berry type is of the same cultivar,
picked at about the same degree of ripeness, washed
and frozen within 2-4 h of the time of picking, and
freeze-dried under conditions that preserve the
components in the berries. Some of the known
chemopreventive agents in berries include vitamins
A, C, and E and folic acid; calcium and selenium;
beta-carotene, alpha-carotene, and lutein;
polyphenols such as ellagic acid, ferulic acid, p-coumaric
acid, quercetin, and several anthocyanins; and
phytosterols such as beta-sitosterol, stigmasterol,
and kaempferol. In initial bioassays, freeze-dried
STRW, BRB, and BB powders were mixed into AIN-76A
synthetic diet at concentrations of 5% and 10% and
fed to Fischer 344 rats before, during, and after
treatment with the esophageal carcinogen N-nitrosomethylbenzylamine
(NMBA). At 25 wk of the bioassay, all three berry
types were found to inhibit the number of esophageal
tumors (papillomas) in NMBA-treated animals by
24-56% relative to NMBA controls. This inhibition
correlated with reductions in the formation of the
NMBA-induced O6-methylguanine adduct in esophageal
DNA, suggesting that the berries influenced the
metabolism of NMBA leading to reduced DNA damage.
Studies are ongoing to determine the mechanisms by
which berries influence NMBA metabolism and DNA
adduct formation. BRBs and STRWs were also tested in
a postinitiation scheme and were found to inhibit
NMBA-induced esophageal tumorigenesis by 31-64% when
administered in the diet following treatment of the
animals with NMBA. Berries, therefore, inhibit tumor
promotion and progression events as well as tumor
initiation. In vivo mechanistic studies with BRBs
indicate that they reduce the growth rate of
premalignant esophageal cells, in part, through
down-regulation of cyclooxygenase-2 leading to
reduced prostaglandin production and of inducible
nitric oxide synthase leading to reduced
nitrate/nitrite levels in the esophagus. Based upon
the preclinical data on rodents, we have initiated
prevention trials in humans to determine if berries
might exhibit chemopreventive effects in the
esophagus.
Publication Types:
PMID: 16800771 [PubMed - indexed for MEDLINE]
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Role of antioxidants in prophylaxis and therapy:
A pharmaceutical perspective.
Ratnam DV,
Ankola DD,
Bhardwaj V,
Sahana DK,
Kumar MN.
Department of Pharmaceutics, National Institute of
Pharmaceutical Education and Research (NIPER),
Phase-X, S.A.S. Nagar, Mohali, Punjab, India.
Antioxidants are emerging as prophylactic and
therapeutic agents. These are the agents, which
scavenge free radicals otherwise reactive oxygen
species and prevent the damage caused by them. Free
radicals have been associated with pathogenesis of
various disorders like cancer, diabetes,
cardiovascular diseases, autoimmune diseases,
neurodegenerative disorders and are implicated in
aging. Several antioxidants like SOD, CAT,
epigallocatechin-3-O-gallate, lycopene, ellagic
acid, coenzyme Q10, indole-3-carbinol, genistein,
quercetin, vitamin C and vitamin E have been found
to be pharmacologically active as prophylactic and
therapeutic agents for above mentioned diseases.
Antioxidants are part of diet but their
bioavailability through dietary supplementation
depends on several factors. This major drawback of
dietary agents may be due to one or many of the
several factors like poor solubility, inefficient
permeability, instability due to storage of food,
first pass effect and GI degradation. Conventional
dosage forms may not result in efficient formulation
owing to their poor biopharmaceutical properties.
Principles of novel drug delivery systems need to be
applied to significantly improve the performance of
antioxidants. Novel drug delivery systems (NDDS)
would also help in delivery of these antioxidants by
oral route, as this route is of prime importance
when antioxidants are intended for prophylactic
purpose. Implication of NDDS for the delivery of
antioxidants is largely governed by physicochemical
characteristics, biopharmaceutical properties and
pharmacokinetic parameters of the antioxidant to be
formulated. Recently, chemical modifications,
coupling agents, liposomes, microparticles,
nanoparticles and gel-based systems have been
explored for the delivery of these difficult to
deliver molecules. Results from several studies
conducted across the globe are positive and provided
us with new anticipation for the improvement of
human healthcare.
Publication Types:
PMID: 16790290 [PubMed - indexed for MEDLINE]
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Molecular targets of dietary agents for
prevention and therapy of cancer.
Aggarwal BB,
Shishodia S.
Cytokine Research Laboratory, Department of
Experimental Therapeutics, The University of Texas
M.D. Anderson Cancer Center, Box 143, 1515 Holcombe
Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org
While fruits and vegetables are recommended for
prevention of cancer and other diseases, their
active ingredients (at the molecular level) and
their mechanisms of action less well understood.
Extensive research during the last half century has
identified various molecular targets that can
potentially be used not only for the prevention of
cancer but also for treatment. However, lack of
success with targeted monotherapy resulting from
bypass mechanisms has forced researchers to employ
either combination therapy or agents that interfere
with multiple cell-signaling pathways. In this
review, we present evidence that numerous agents
identified from fruits and vegetables can interfere
with several cell-signaling pathways. The agents
include curcumin (turmeric), resveratrol (red
grapes, peanuts and berries), genistein (soybean),
diallyl sulfide (allium), S-allyl cysteine (allium),
allicin (garlic), lycopene (tomato), capsaicin (red
chilli), diosgenin (fenugreek), 6-gingerol (ginger),
ellagic acid (pomegranate), ursolic acid (apple,
pears, prunes), silymarin (milk thistle), anethol
(anise, camphor, and fennel), catechins (green tea),
eugenol (cloves), indole-3-carbinol (cruciferous
vegetables), limonene (citrus fruits), beta carotene
(carrots), and dietary fiber. For instance, the
cell-signaling pathways inhibited by curcumin alone
include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L),
caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2,
and 5-LOX. The active principle identified in fruit
and vegetables and the molecular targets modulated
may be the basis for how these dietary agents not
only prevent but also treat cancer and other
diseases. This work reaffirms what Hippocrates said
25 centuries ago, let food be thy medicine and
medicine be thy food.
Publication Types:
PMID: 16563357 [PubMed - indexed for MEDLINE]
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Urolithins, ellagic acid-derived metabolites
produced by human colonic microflora, exhibit
estrogenic and antiestrogenic activities.
Larrosa M,
González-Sarrías A,
García-Conesa MT,
Tomás-Barberán FA,
Espín JC.
Research Group on Quality, Safety and Bioactivity of
Plant Foods. Department of Food Science and
Technology, CEBAS-CSIC, P.O. Box 164, 30100 Campus
de Espinardo, Murcia, Spain.
Urolithins A and B
(hydroxy-6H-dibenzo[b,d]pyran-6-one derivatives) are
colonic microflora metabolites recently proposed as
biomarkers of human exposure to dietary ellagic acid
derivatives. Molecular models suggest that
urolithins could display estrogenic and/or
antiestrogenic activity. To this purpose, both
urolithins and other known phytoestrogens (genistein,
daidzein, resveratrol, and enterolactone) were
assayed to evaluate the capacity to induce cell
proliferation on the estrogen-sensitive human breast
cancer MCF-7 cells as well as the ability to bind to
alpha- and beta-estrogen receptors. Both urolithins
A and B showed estrogenic activity in a
dose-dependent manner even at high concentrations
(40 microM), without antiproliferative or toxic
effects, whereas the other phytoestrogens inhibited
cell proliferation at high concentrations. Overall,
urolithins showed weaker estrogenic activity than
the other phytoestrogens. However, both urolithins
displayed slightly higher antiestrogenic activity
(antagonized the growth promotion effect of
17-beta-estradiol in a dose-dependent manner) than
the other phytoestrogens. The IC(50) values for the
ERalpha and ERbeta binding assays were 0.4 and 0.75
microM for urolithin A; 20 and 11 microM for
urolithin B; 3 and 0.02 for genistein; and 2.3 and 1
for daidzein, respectively; no binding was detected
for resveratrol and enterolactone. Urolithins A and
B entered into MCF-7 cells and were metabolized to
yield mainly urolithin-sulfate derivatives. These
results, together with previous studies regarding
absorption and metabolism of dietary ellagitannins
and ellagic acid in humans, suggest that the gut
microflora metabolites urolithins are potential
endocrine-disrupting molecules, which could resemble
other described "enterophytoestrogens" (microflora-derived
metabolites with estrogenic/antiestrogenic
activity). Further research is warranted to evaluate
the possible role of ellagitannins and ellagic acid
as dietary "pro-phytoestrogens".
Publication Types:
PMID: 16506809 [PubMed - indexed for MEDLINE]
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Pomegranate juice, total pomegranate
ellagitannins, and punicalagin suppress inflammatory
cell signaling in colon cancer cells.
Adams LS,
Seeram NP,
Aggarwal BB,
Takada Y,
Sand D,
Heber D.
Center for Human Nutrition, David Geffen School of
Medicine, University of California, Los Angeles,
California 90095, USA. ladams@mednet.ucla.edu
Phytochemicals from fruits such as the pomegranate (Punica
granatum L) may inhibit cancer cell proliferation
and apoptosis through the modulation of cellular
transcription factors and signaling proteins. In
previous studies, pomegranate juice (PJ) and its
ellagitannins inhibited proliferation and induced
apoptosis in HT-29 colon cancer cells. The present
study examined the effects of PJ on inflammatory
cell signaling proteins in the HT-29 human colon
cancer cell line. At a concentration of 50 mg/L PJ
significantly suppressed TNFalpha-induced COX-2
protein expression by 79% (SE = 0.042), total
pomegranate tannin extract (TPT) 55% (SE = 0.049),
and punicalagin 48% (SE = 0.022). Additionally, PJ
reduced phosphorylation of the p65 subunit and
binding to the NFkappaB response element 6.4-fold.
TPT suppressed NFkappaB binding 10-fold, punicalagin
3.6-fold, whereas ellagic acid (EA) (another
pomegranate polyphenol) was ineffective. PJ also
abolished TNFalpha-induced AKT activation, needed
for NFkappaB activity. Therefore, the polyphenolic
phytochemicals in the pomegranate can play an
important role in the modulation of inflammatory
cell signaling in colon cancer cells.
Publication Types:
PMID: 16448212 [PubMed - indexed for MEDLINE]
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The dietary hydrolysable tannin punicalagin
releases ellagic acid that induces apoptosis in
human colon adenocarcinoma Caco-2 cells by using the
mitochondrial pathway.
Larrosa M,
Tomás-Barberán FA,
Espín JC.
Research Group on Quality, Safety and Bioactivity of
Plant Foods, Department of Food Science and
Technology, Campus de Espinardo, Espinardo, Murcia,
Spain.
Polyphenol-rich dietary foodstuffs have attracted
attention due to their cancer chemopreventive and
chemotherapeutic properties. Ellagitannins (ETs)
belong to the so-called hydrolysable tannins found
in strawberries, raspberries, walnuts, pomegranate,
oak-aged red wine, etc. Both ETs and their
hydrolysis product, ellagic acid (EA), have been
reported to induce apoptosis in tumour cells.
Ellagitannins are not absorbed in vivo but reach the
colon and release EA that is metabolised by the
human microflora. Our aim was to investigate the
effect of a dietary ET [pomegranate punicalagin (PUNI)]
and EA on human colon cancer Caco-2 and colon normal
CCD-112CoN cells. Both PUNI and EA provoked the same
effects on Caco-2 cells: down-regulation of cyclins
A and B1 and upregulation of cyclin E, cell-cycle
arrest in S phase, induction of apoptosis via
intrinsic pathway (FAS-independent, caspase
8-independent) through bcl-XL down-regulation with
mitochondrial release of cytochrome c into the
cytosol, activation of initiator caspase 9 and
effector caspase 3. Neither EA nor PUNI induced
apoptosis in normal colon CCD-112CoN cells (no
chromatin condensation and no activation of caspases
3 and 9 were detected). In the case of Caco-2 cells,
no specific effect can be attributed to PUNI since
it was hydrolysed in the medium to yield EA, which
entered into the cells and was metabolised to
produce dimethyl-EA derivatives. Our study suggests
that the anticarcinogenic effect of dietary ETs
could be mainly due to their hydrolysis product, EA,
which induced apoptosis via mitochondrial pathway in
colon cancer Caco-2 cells but not in normal colon
cells.
Publication Types:
PMID: 16426830 [PubMed - indexed for MEDLINE]
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Current trends and perspectives in nutrition and
cancer prevention.
Bárta I,
Smerák P,
Polívková Z,
Sestáková H,
Langová M,
Turek B,
Bártová J.
Center of Biomedical Sciences, Division of General
Biology and Genetics, Charles University, 3rd
Faculty of Medicine, Prague, Czech Republic.
ivo.barta@lf3.cuni.cz
There is an increasing evidence that dietary
phytochemicals may play important roles as
chemopreventive or chemotherapeutic agents in
prevention of many diseases, including tumors. The
purpose of this study was to examine antimutagenic
effects and effect on the immune response of
representative series of substances which commonly
occur in human diet. Using the Ames bacterial
mutagenicity test and in vivo chemiluminescence
test, we investigated antigenotoxic and
immunomodulatory effects of juices and vegetable
homogenates (carrot + cauliflower, cauliflower, red
cabbage, broccoli, onion, garlic) on the
genotoxicity of AFB1 and pyrolysates of aminoacids.
Using the Ames test and in vivo micronucleus, the
chemiluminescence test, the blastic transformation
test and the comet assay we examined antimutagenic
effects of chemically identified chemoprotective
substances in the pure form (resveratrol,
diallylsulphide, phenethyl isothiocyanate, ellagic
acid, epigallocatechin gallate, genistein and
curcumin) on mutagenicity induced by three reference
mutagens: aflatoxin B1 (AFB1),
2-amino-3-metylimidazo[4,5,-f] chinolin (IQ) and N-nitroso-
N-metylurea (MNU) and effect of phytochemicals on
the immunosuppression caused by these mutagens. All
complete vegetable homogenates and substances of
plant origin tested, showed a clear antimutagenic
and immunomodulatory activities on mutagenicity and
immunosuppression induced by reference mutagens.
Only in the Ames test the effect of some
phytochemicals against direct mutagen MNU was lower
compared to indirect mutagens AFB1 and IQ.
Similarly, resveratrol and epigallocatechin gallate
had no inhibitory effect on mutagenicity MNU in the
Ames test.
Publication Types:
PMID: 16416008 [PubMed - indexed for MEDLINE]
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Evaluation of estrogenic/antiestrogenic activity
of ellagic acid via the estrogen receptor subtypes
ERalpha and ERbeta.
Papoutsi Z,
Kassi E,
Tsiapara A,
Fokialakis N,
Chrousos GP,
Moutsatsou P.
Department of Biological Chemistry, Medical School,
University of Athens Mikras Asias Str 75, Goudi,
Athens 11527, Greece.
Ellagic acid is a plant-derived polyphenol,
possessing antioxidant, antiproliferative, and
antiatherogenic properties. Whether this compound
has estrogenic/antiestrogenic activity, however,
remains largely unknown. To answer this question, we
first investigated the ability of ellagic acid to
influence the activity of the estrogen receptor
subtypes ERalpha and ERbeta in HeLa cells. Cells co-transfected
with an estrogen response element (ERE)-driven
luciferase (Luc) reporter gene and an ERalpha- or
ERbeta-expression vector were exposed to graded
concentrations of ellagic acid. At low
concentrations (10(-7) to 10(-9) M), this compound
displayed a small but significant estrogenic
activity via ERalpha, whereas it was a complete
estrogen antagonist via ERbeta. Further evaluation
revealed that ellagic acid was a potent antiestrogen
in MCF-7 breast cancer-derived cells, increasing,
like the pure estrogen antagonist ICI182780, IGFBP-3
levels. Moreover, ellagic acid induced nodule
mineralization in an osteoblastic cell line (KS483),
an effect that was abolished by the estrogen
antagonist. Endometrium-derived epithelial cells
(Ishikawa) showed no response to the natural
compound by using a cell viability assay (MTT).
These findings suggest that ellagic acid may be a
natural selective estrogen receptor modulator (SERM).
Publication Types:
PMID: 16190622 [PubMed - indexed for MEDLINE]
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In vitro antiproliferative, apoptotic and
antioxidant activities of punicalagin, ellagic acid
and a total pomegranate tannin extract are enhanced
in combination with other polyphenols as found in
pomegranate juice.
Seeram NP,
Adams LS,
Henning SM,
Niu Y,
Zhang Y,
Nair MG,
Heber D.
Center for Human Nutrition, David Geffen School of
Medicine, University of California, Los Angeles, CA
90095, USA. nseeram@mednet.ucla.edu
Pomegranate (Punica granatum L.) fruits are widely
consumed as juice (PJ). The potent antioxidant and
anti-atherosclerotic activities of PJ are attributed
to its polyphenols including punicalagin, the major
fruit ellagitannin, and ellagic acid (EA).
Punicalagin is the major antioxidant polyphenol
ingredient in PJ. Punicalagin, EA, a standardized
total pomegranate tannin (TPT) extract and PJ were
evaluated for in vitro antiproliferative, apoptotic
and antioxidant activities. Punicalagin, EA and TPT
were evaluated for antiproliferative activity at
12.5-100 microg/ml on human oral (KB, CAL27), colon
(HT-29, HCT116, SW480, SW620) and prostate (RWPE-1,
22Rv1) tumor cells. Punicalagin, EA and TPT were
evaluated at 100 microg/ml concentrations for
apoptotic effects and at 10 microg/ml concentrations
for antioxidant properties. However, to evaluate the
synergistic and/or additive contributions from other
PJ phytochemicals, PJ was tested at concentrations
normalized to deliver equivalent amounts of
punicalagin (w/w). Apoptotic effects were evaluated
against the HT-29 and HCT116 colon cancer cell
lines. Antioxidant effects were evaluated using
inhibition of lipid peroxidation and Trolox
equivalent antioxidant capacity (TEAC) assays.
Pomegranate juice showed greatest antiproliferative
activity against all cell lines by inhibiting
proliferation from 30% to 100%. At 100 microg/ml, PJ,
EA, punicalagin and TPT induced apoptosis in HT-29
colon cells. However, in the HCT116 colon cells, EA,
punicalagin and TPT but not PJ induced apoptosis.
The trend in antioxidant activity was PJ>TPT>punicalagin>EA.
The superior bioactivity of PJ compared to its
purified polyphenols illustrated the multifactorial
effects and chemical synergy of the action of
multiple compounds compared to single purified
active ingredients.
Publication Types:
PMID: 15936648 [PubMed - indexed for MEDLINE]
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Enhancement of radiation-induced oxidative stress
and cytotoxicity in tumor cells by ellagic acid.
Bhosle SM,
Huilgol NG,
Mishra KP.
Radiation Oncology Division, Dr. Balabhai Nanavati
Hospital, Mumbai 400 056, India.
BACKGROUND: Failure of treatment of cancer in clinic
by radio/chemotherapy is generally attributed to
tumor resistance. It is, therefore, important to
develop strategies to increase the cytotoxicity of
tumor cells by radiation in combination with new
tumor selective cytotoxic agents. We describe the
role of ellagic acid (EA) and gamma radiation on the
oxidative stress and subsequent cytotoxicity of
tumor cells in vitro as well as in vivo and their
sparing effects on normal cells. METHODS: Ehrlich
ascites carcinoma (EAC)-transplanted Swiss mice were
intraperitoneally injected with EA followed by
radiation treatment of 2 Gy for 4 alternate days.
Hela cells were used for in vitro studies. Reactive
oxygen species (ROS) level was measured by
spectrofluorimetric method by using 2,
7-dichlorodihydrofluoresceindiacetate (DCHFDA)
fluorescent probe. Cytotoxicity was measured by
Trypan blue dye exclusion test and mitochondrial
potential was measured using Rhodamine 123 as a
probe. Antioxidant enzymes were measured by
spectrophotometric methods. RESULTS: EA was found to
generate ROS in tumor cells, which increased, by an
order of magnitude when cells were treated with EA
in combination with gamma radiation. The decrease in
mitochondrial potential and the loss of cell
viability were remarkably greater in tumor cells
from mice treated with EA and radiation than alone
treatment with either of them. Moreover, EA was
found to protect against radiation-induced oxidative
stress in splenic lymphocytes of tumor-transplanted
mice. Measurement of antioxidant enzymes such as
superoxide dismutase (SOD), catalase, glutathione
peroxidase (GSH-Px) and glutathione reductase (GR)
in tumor cells showed decrease after treatment with
EA and radiation in vivo. Treatment of tumor bearing
mice with EA and radiation showed significant
decrease in animal's body weight suggesting reduced
tumor burden. CONCLUSION: Combined treatment of
tumor with EA and radiation enhances oxidative
stress and cytotoxicity in tumor cells. EA protects
normal cells against radiation damage. This may
offer potential therapeutic benefit, which warrants
clinical study for application in cancer
radiotherapy.
Publication Types:
PMID: 15922998 [PubMed - indexed for MEDLINE]
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The dietary polyphenol ellagic acid is a potent
inhibitor of hOAT1.
Whitley AC,
Sweet DH,
Walle T.
Department of Cell and Molecular Pharmacology and
Experimental Therapeutics, Medical University of
South Carolina, 173 Ashley Avenue, Charleston, SC
29425, USA. wallet@musc.edu
Ellagic acid (EA), a polyphenol present in berries,
has been demonstrated to be preventive of esophageal
and colon cancer in animals. Here, we have studied
the ability of organic anion transporters (OATs) and
organic anion-transporting polypeptides (OATPs) to
transport EA. The accumulation of radiolabeled
(14)C]EA, [(3)H]p-aminohippuric acid (PAH),
[(14)C]glutarate, [(3)H]estrone sulfate,
[(3)H]ochratoxin A, and [(3)H]taurocholic acid +/-
inhibitor(s) was tested in OAT- and OATP-expressing
oocytes. Oocytes expressing human (h)OAT1, rat
(r)Oat1, and hOAT4 accumulated 6.5-, 7.1-, and
8.9-fold more EA, respectively, than did
water-injected oocytes. This accumulation was
prevented by the prototype OAT inhibitors
bromosulfophthalein and probenecid. rOatp1, mouse
(m)Oat2, hOAT3, and mOat5 showed no EA transport.
The uptake of the prototype OAT substrate PAH in
hOAT1-expressing oocytes was dose dependently and
potently inhibited by EA with an IC(50)of 207 nM. In
conclusion, we have demonstrated that the OAT family
members hOAT1, rOat1, and hOAT4 mediate transport of
EA, with a very high affinity for hOAT1.
Publication Types:
PMID: 15870380 [PubMed - indexed for MEDLINE]
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Ellagic acid induced p53/p21 expression, G1
arrest and apoptosis in human bladder cancer T24
cells.
Li TM,
Chen GW,
Su CC,
Lin JG,
Yeh CC,
Cheng KC,
Chung JG.
School of Chinese Medicine, China Medical
University, Taichung City 400, Taiwan, ROC.
It is well known that dietary phenolic compounds can
elicit vital cellular responses such as cytotoxicity,
cell cycle arrest and apoptosis by activating a
cascade of molecular events. Ellagic acid is one of
these phenolic compounds, but the exact mechanism of
its action is still unclear. The objective of this
study was to investigate ellagic acid-induced cell
cycle arrest and apoptosis in T24 human bladder
cancer cells in vitro. Assays were performed to
determine cell viability, cell cycle arrest,
apoptosis, caspases-3 activity and gene expression,
measured by flow cytometric assay, polymerase chain
reaction (PCR) and determination of caspase-3
activity. Ellagic acid significantly reduced the
viable cells, induced G0/G1-phase arrest of the cell
cycle and apoptosis. Ellagic acid also increased p53
and p21 and decreased CDK2 gene expression, that may
lead to the G0/G1 arrest of T24 cells. Ellagic acid
also promoted caspase-3 activity after exposure for
1, 3, 6, 12 and 24 h, which led to induction of
apoptosis. Furthermore, the ellagic acid-induced
apoptosis on T24 cells was blocked by the
broad-spectrum caspase inhibitor (z-VAD-fmk).
Publication Types:
PMID: 15868936 [PubMed - indexed for MEDLINE]
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Inhibition of the growth of premalignant and
malignant human oral cell lines by extracts and
components of black raspberries.
Han C,
Ding H,
Casto B,
Stoner GD,
D'Ambrosio SM.
Department of Radiology, The Ohio State University,
Columbus 43210, USA.
Black raspberries are a rich natural source of
chemopreventive phytochemicals. Recent studies have
shown that freeze-dried black raspberries inhibit
the development of oral, esophageal, and colon
cancer in rodents, and extracts of black raspberries
inhibit benzo(a)pyrene-induced cell transformation
of hamster embryo fibroblasts. However, the
molecular mechanisms and the active components
responsible for black raspberry chemoprevention are
unclear. In this study, we found that 2 major
chemopreventive components of black raspberries,
ferulic acid and beta-sitosterol, and a fraction
eluted with ethanol (RO-ET) during silica column
chromatography of the organic extract of
freeze-dried black raspberries inhibit the growth of
premalignant and malignant but not normal human oral
epithelial cell lines. Another fraction eluted with
CH2Cl2/ethanol (DM:ET) and ellagic acid inhibited
the growth of normal as well as premalignant and
malignant human oral cell lines. We investigated the
molecular mechanisms by which ferulic acid and beta-sitosterol
and the RO-ET fraction selectively inhibited the
growth of premalignant and malignant oral cells
using flow cytometry and Western blotting of cell
cycle regulatory proteins. There was no discernable
change in the cell cycle distribution following
treatment of cells with the RO-ET fraction.
Premalignant and malignant cells redistributed to
the G2/M phase of the cell cycle following
incubation with ferulic acid. beta-sitosterol
treated premalignant and malignant cells accumulated
in the G0/G1 and G2/M phases, respectively. The
RO-ET fraction reduced the levels of cyclin A and
cell division cycle gene 2 (cdc2) in premalignant
cells and cyclin B1, cyclin D1, and cdc2 in the
malignant cell lines. This fraction also elevated
the levels of p21waf1/cip1 in the malignant cell
line. Ferulic acid treatment led to increased levels
of cyclin B1 and cdc2 in both cell lines, and
p21waf1/cip1 was induced in the malignant cell line.
beta-sitosterol reduced the levels of cyclin B1 and
cdc2 while increasing p21waf1/cip1 in both the
premalignant and malignant cell lines. These results
show for the first time that the growth inhibitory
effects of black raspberries on premalignant and
malignant human oral cells may reside in specific
components that target aberrant signaling pathways
regulating cell cycle progression.
Publication Types:
PMID: 15860443 [PubMed - indexed for MEDLINE]
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Cancer preventive role of selected dietary
factors.
Ray A.
The Hormel Institute, University of Minnesota,
801-16th Avenue NE, Austin, MN 55912, USA. amitraym@rediffmail.com
Dietary behavior seems to be an important modifiable
determinant for the risk of cancer. The evidences
from several epidemiological studies suggest that
higher intakes of fruits and vegetables have been
associated with lower risk of cancer. Dietary
phenolic and polyphenolic substances, terpenoids,
dietary fibers, fish oils, some micronutrients
present in foods of both plant and animal origin,
and a reduction of caloric intake appear to inhibit
the process of cancer development. Many dietary
factors possess antioxidant and anti-inflammatory
properties and cause induction of phase II enzymes
like glutathione-S-transferases. It has been
suggested that cruciferous vegetables play an
important role in cancer prevention, and their
chemopreventive effects are due to high
glucosinolate content which under enzymatic
hydrolysis produces bioactive compound
isothiocyanates. Further, isothiocyanates of a wide
variety of cruciferous vegetables are powerful
inhibitors of carcinogenesis in experimental animal
models. Several flavonoids present in fruits, tea,
soya beans, etc. may be useful as cancer preventive
agents. Similarly, ellagic acid, perillyl alcohol
and resveratrol found in various fruits may have
chemoprotective effect. Moreover, different
vanilloids such as curcumin and gingerol have been
shown to possess antioxidative properties.
Nevertheless, in spite of several studies, still the
effects of various ingredients are not clearly
distinguished. In human, little convincing evidence
has been established for the proposed protective
effects of dietary constituents. It is an important
future research goal to provide necessary evidences
to support the chemopreventive role of different
dietary factors, and also to clarify
misunderstandings in this perplexing area.
Publication Types:
PMID: 15805687 [PubMed - indexed for MEDLINE]
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Correlation of in vitro chemopreventive efficacy
data from the human epidermal cell assay with animal
efficacy data and clinical trial plasma levels.
Elmore E,
Siddiqui S,
Navidi M,
Steele VE,
Redpath JL.
Department of Radiation Oncology, University of
California Irvine, Irvine, CA 92697, USA. eelmore@uci.edu
The human epidermal cell (HEC) assay, which uses
carcinogen exposed normal skin keratinocytes to
screen for cancer prevention efficacy, was used to
screen possible preventive agents. The endpoints
measured were inhibition of carcinogen-induced
growth and induction of involucrin, an early marker
of differentiation. Sixteen of twenty agents (apigenin,
apomine, budesonide, N-(2-carboxyphenyl)retinamide,
ellagic acid, ibuprofen, indomethacin, melatonin,
(-)-2-oxo-4-thiazolidine carboxylic acid, polyphenon
E, resveratrol, beta-sitosterol, sulfasalazine,
vitamin E acetate, and zileuton) were positive in at
least one of the two assay endpoints. Four agents
(4-methoxyphenol, naringenin, palmitoylcarnitine
chloride, and silymarin) were negative in the assay.
Nine of the sixteen agents were positive for both
endpoints. Agents that showed the greatest response
included: ellagic acid > budesonide, ibuprofen >
apigenin, and quinicrine dihydrochloride.
Fifty-eight of sixty-five agents that have been
evaluated in the HEC assay have also been evaluated
in one or more rodent bioassays for cancer
prevention and several are in clinical trials for
cancer prevention. The assay has an overall
predictive accuracy of approximately 91.4% for
efficacy in rodent cancer prevention irrespective of
the species used, the tissue model, or the
carcinogen used. Comparison of the efficacious
concentrations in vitro to plasma levels in clinical
trials show that concentrations that produced
efficacy in the HEC assay were achieved in clinical
studies for 31 of 33 agents for which plasma levels
and/or C(max) levels were available. For two agents,
9-cis-retinoic acid (RA) and dehydroepiandrosterone
(DHEA), the plasma levels greatly exceeded the
highest concentration (HC) found to have efficacy in
vitro. Thus, the HEC assay has an excellent
predictive potential for animal efficacy and is
responsive at clinically achievable concentrations.
(c) 2005 Wiley-Liss, Inc.
Publication Types:
PMID: 15786488 [PubMed - indexed for MEDLINE]
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Support ellagic acid therapy in patients with
hormone refractory prostate cancer (HRPC) on
standard chemotherapy using vinorelbine and
estramustine phosphate.
Falsaperla M,
Morgia G,
Tartarone A,
Ardito R,
Romano G.
Operative Unit of Urology, Centro di Riferimento
Oncologico della Basilicata, Rionero in Vulture,
Potenza, Italy. mayurol@yahoo.it
BACKGROUND: Recent phase III studies in hormone
refractory prostate cancer (HRPC) showed an
improvement in terms of overall survival (OS),
objective response (OR) and biochemical response
(BR); however, chemotherapy is usually accompanied
by negative side effects that determines poor
quality of life (QoL) and only marginally improves
individual clinical response (ICR) in terms of pain
relief and performance status. Ellagic acid is a
polyphenol that is found in many species of
flowering plants. It is an antioxidant that
determines apoptosis, down regulation of IGF-II,
activates p21 (waf1/Cip1), mediates the cumulative
effect on G1/S transition phase and prevents
destruction of p-53 gene by cancer cells. ENDPOINTS:
The aim of this study was to assess the effects of
ellagic acid support therapy on toxicity, OR, ICR
and BR in HRPC patients treated with estramustine
phosphate and vinorelbine. MATERIALS AND METHODS:
Patients with HRPC were randomly distributed in two
study groups: a control group (group A) who
underwent chemotherapy with vinorelbine and
estramustine phosphate, and an experimental group
(group B) where chemotherapy regimen was associated
with ellagic acid. RESULTS: The mean number of
chemotherapy cycles/patient was 4 (range 3-8 cycles)
and 6.5 (range 5-11) in group A and B patients,
respectively. A reduction in systemic toxicity,
statistically significant for neutropenia,
associated with better results in term of OR rate,
ICR, and BR were observed in group B compared with
group A. On the contrary no significant difference
in OS and PFS was detected between groups.
CONCLUSIONS: our study suggests that the use of
ellagic acid as support therapy reduces chemotherapy
induced toxicity, in particular neutropenia, in HRCP
patients; however, further studies are required to
confirm our results.
Publication Types:
PMID: 15774240 [PubMed - indexed for MEDLINE]
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