Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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41:
Invest New Drugs. 2005
Mar;23(2):121-2.
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Erratum in:
Pomegranate (Punica granatum)
pure chemicals show possible synergistic
inhibition of human PC-3 prostate cancer cell
invasion across Matrigel.
Lansky EP,
Harrison G,
Froom P,
Jiang WG.
Rimonest Ltd., P.O.B. 9945, Haifa, Israel.
Four pure chemicals, ellagic acid (E), caffeic
acid (C), luteolin (L) and punicic acid (P), all
important components of the aqueous compartments
or oily compartment of pomegranate fruit (Punica
granatum), and each belonging to different
representative chemical classes and showing known
anticancer activities, were tested as potential
inhibitors of in vitro invasion of human PC-3
prostate cancer cells in an assay employing
Matrigel artificial membranes. All compounds
significantly inhibited invasion when employed
individually. When C, P, and L were equally
combined at the same gross dosage (4 microg/ml) as
when the compounds were tested individually, a
supradditive inhibition of invasion was observed,
measured by the Kruskal-Wallis non-parametric
test.
PMID: 15744587 [PubMed - indexed for MEDLINE]
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Identification and
quantification of polyphenolic compounds in Longan
(Euphoria longana Lam.) fruit.
Rangkadilok N,
Worasuttayangkurn L,
Bennett RN,
Satayavivad J.
Laboratory of Pharmacology, Chulabhorn Research
Institute (CRI), Vipavadee-Rangsit Highway, Laksi,
Bangkok 10210, Thailand.
Regular consumption of fruit and vegetables is
associated with a lower risk of some chronic
diseases including various forms of cancer and
cardiovascular diseases. The health-promoting
potential of these foods may be due, in part, to
the phytochemical bioactive compounds present in
the plants. Fruit of Euphoria longana Lam. (longan)
are consumed throughout Asia and are a major crop
in Thailand. In the present study phytochemicals
were extracted with 70% methanol from peel, pulp,
and seed tissues of longan fruit, and the major
components were identified as gallic acid,
corilagin (an ellagitannin), and ellagic acid. A
high-through-put reversed phase HPLC method was
developed to determine the content of these three
compounds in different parts of the longan fruit
and among different cultivars. The analyses showed
that there was a large variation in the contents
of gallic acid, corilagin, and ellagic acid in
different plant tissues and cultivars. Seed
contained the highest levels of the three
phenolics, and pulp contained the lowest. Among
commercial cultivars, Biewkiew and Edor contained
the highest levels of gallic and ellagic acid
while Srichompoo contained the highest content of
corilagin. These three cultivars may be used in
directed breeding and cultivation programs and to
develop concentrated longan seed extracts to
promote good health. Utilization of this byproduct
material will support the use of thousands of tons
of waste longan seeds after the production of
canned longan pulp.
Publication Types:
PMID: 15740011 [PubMed - indexed for MEDLINE]
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Ellagic acid potentiates the
effect of quercetin on p21waf1/cip1, p53, and MAP-kinases
without affecting intracellular generation of
reactive oxygen species in vitro.
Mertens-Talcott SU,
Bomser JA,
Romero C,
Talcott ST,
Percival SS.
Department of Food Science and Human Nutrition,
Institute of Food and Agricultural Sciences,
University of Florida, Gainesville, FL 32611-0370,
USA.
Anticarcinogenic effects attributed to polyphenols
in fruits may be based on synergistic, additive,
or antagonistic interactions of many compounds. In
a previous study, it was demonstrated that
quercetin and ellagic acid interacted
synergistically in the induction of apoptosis in
the human leukemia cell line, MOLT-4. To
investigate possible cellular mechanisms, this
study evaluated whether synergistic effects might
be detectable within proapoptotic or
antiproliferative signal transduction pathways. We
found that quercetin and combinations of quercetin
and ellagic acid nonsynergistically increased p53
protein levels. In contrast, ellagic acid
potentiated the effects of quercetin for
p21(cip1/waf1) protein levels and p53
phosphorylation at serine 15, possibly explaining
the synergistic effect observed in apoptosis
induction. Phosphorylation of the mitogen-activated
protein (MAP) kinases, c-jun N-terminal (JNK)1,2
and p38, was also increased by the combination of
ellagic acid and quercetin, whereas quercetin
alone induced only p38. We further evaluated
whether the generation of reactive oxygen species
(ROS) and/or quercetin stability were influenced
by interactions of ellagic acid with quercetin.
Quercetin increased the generation of ROS, which
was neither potentiated nor inhibited by ellagic
acid. The stability of intracellular and
extracellular quercetin was not influenced by the
presence of ellagic acid. In summary, quercetin
and ellagic acid combined increase the activation
of p53 and p21(cip1/waf1) and the MAP kinases,
JNK1,2 and p38, in a more than additive manner,
suggesting a mechanism by which quercetin and
ellagic acid synergistically induce apoptosis in
cancer cells.
Publication Types:
PMID: 15735102 [PubMed - indexed for MEDLINE]
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Ellagic acid and quercetin
interact synergistically with resveratrol in the
induction of apoptosis and cause transient cell
cycle arrest in human leukemia cells.
Mertens-Talcott SU,
Percival SS.
Department of Food Science and Human Nutrition,
Institute of Food and Agricultural Sciences,
University of Florida, P.O. Box 110370,
Gainesville, FL 32611-0370, USA.
Anticarcinogenic effects of polyphenolic compounds
in fruits and vegetables are well established.
Although polyphenols naturally occur as
combinations, little information is available
regarding possible synergistic or antagonistic
biochemical interactions between compounds.
Identifying potential interactions between
polyphenols may provide information regarding the
efficiency of polyphenol-containing foods in
cancer prevention. The objective of this study was
to investigate the interactions of ellagic acid
and quercetin with resveratrol, polyphenols which
occur in muscadine grapes, with the hypothesis
that the selected polyphenols would interact
synergistically in the induction of apoptosis and
reduction of cell growth in human leukemia cells
(MOLT-4). To test this hypothesis, alterations in
cell cycle kinetics, proliferation, and apoptosis
(caspase-3 activity) were examined after
incubation with ellagic acid, quercetin, and
resveratrol as single compounds and in
combination. Results showed a more than additive
interaction for the combination of ellagic acid
with resveratrol and furthermore, significant
alterations in cell cycle kinetics induced by
single compounds and combinations were observed.
An isobolographic analysis was performed to assess
the apparent synergistic interaction for the
combinations of ellagic acid with resveratrol and
quercetin with resveratrol in the induction of
caspase 3 activity, confirming a synergistic
interaction with a combination index of 0.64 for
the combination of ellagic acid and resveratrol
and 0.68 for quercetin and resveratrol. Results
indicate that the anticarcinogenic potential of
foods containing polyphenols may not be based on
the effects of individual compounds, but may
involve a synergistic enhancement of the
anticancer effects.
Publication Types:
PMID: 15670891 [PubMed - indexed for MEDLINE]
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Combined inhibition of PDGF and
VEGF receptors by ellagic acid, a dietary-derived
phenolic compound.
Labrecque L,
Lamy S,
Chapus A,
Mihoubi S,
Durocher Y,
Cass B,
Bojanowski MW,
Gingras D,
Béliveau R.
Laboratoire de Médecine Moléculaire, Hôpital
Ste-Justine-Université du Québec à Montréal,
Centre de Cancérologie Charles-Bruneau, 3175
Chemin Côte-Ste-Catherine, Montréal, Québec,
Canada H3T 1C5.
The vascular endothelial growth factor (VEGF) and
platelet-derived growth factor (PDGF) receptors
play essential and complementary roles in
angiogenesis and combined inhibition of these
receptors has been shown to result in potent
antitumor activity in vivo. In this study, we
report that ellagic acid (EA), a natural
polyphenol found in fruits and nuts, inhibits VEGF-induced
phosphorylation of VEGFR-2 in endothelial cell
(EC) as well as PDGF-induced phosphorylation of
PDGFR in smooth muscle cells, leading to the
inhibition of downstream signaling triggered by
these receptors. EA also specifically inhibited
VEGF-induced migration of ECs as well as their
differentiation into capillary-like tubular
structures and abolished PDGF-dependent smooth
muscle cell migration. Interestingly, EA presents
a greater selectivity for normal cells than for
tumor cells since the migration of the U87 and
HT1080 cell lines were much less affected by this
molecule. The identification of EA as a naturally
occurring dual inhibitor of VEGF and PDGF
receptors suggests that this molecule possesses
important antiangiogenic properties that may be
helpful for the prevention and treatment of
cancer.
Publication Types:
PMID: 15661805 [PubMed - indexed for MEDLINE]
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Suppression of the nuclear
factor-kappaB activation pathway by spice-derived
phytochemicals: reasoning for seasoning.
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
The activation of nuclear transcription factor
kappaB has now been linked with a variety of
inflammatory diseases, including cancer,
atherosclerosis, myocardial infarction, diabetes,
allergy, asthma, arthritis, Crohn's disease,
multiple sclerosis, Alzheimer's disease,
osteoporosis, psoriasis, septic shock, and AIDS.
Extensive research in the last few years has shown
that the pathway that activates this transcription
factor can be interrupted by phytochemicals
derived from spices such as turmeric (curcumin),
red pepper (capsaicin), cloves (eugenol), ginger (gingerol),
cumin, anise, and fennel (anethol), basil and
rosemary (ursolic acid), garlic (diallyl sulfide,
S-allylmercaptocysteine, ajoene), and pomegranate
(ellagic acid). For the first time, therefore,
research provides "reasoning for seasoning."
Publication Types:
PMID: 15659827 [PubMed - indexed for MEDLINE]
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Metabolism of antioxidant and
chemopreventive ellagitannins from strawberries,
raspberries, walnuts, and oak-aged wine in humans:
identification of biomarkers and individual
variability.
Cerdá B,
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.
Ellagitannins (ETs) are dietary polyphenols,
containing ellagic acid (EA) subunits, with
antioxidant and cancer chemopreventive activities
that might contribute to health benefits in
humans. However, little is known about their
metabolic fate. We investigate here the metabolism
of different dietary ETs and EA derivatives in
humans. Forty healthy volunteers were distributed
in four groups. Each group consumed, in a single
dose, a different ET-containing foodstuff, i.e.,
strawberries (250 g), red raspberries (225 g),
walnuts (35 g), and oak-aged red wine (300 mL).
After the intake, five urine fractions (F) were
collected at 8 (F1), 16 (F2), 32 (F3), 40 (F4),
and 56 (F5) h. Neither ETs nor EA were detected in
urine after LC-MS/MS analysis. However, the
microbial metabolite
3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (urolithin
B) conjugated with glucuronic acid was detected
along the fractions F3-F5 in all of the subjects,
independently of the consumed foodstuff. The mean
percentage of metabolite excretion ranged from 2.8
(strawberries) to 16.6% (walnuts) regarding the
ingested ETs. Considerable interindividual
differences were noted, identifying "high and low
metabolite excreters" in each group, which
supported the involvement of the colonic
microflora in ET metabolism. These results
indicate that urolithin B (a previously described
antiangiogenic and hyaluronidase inhibitor
compound) is a biomarker of human exposure to
dietary ETs and may be useful in intervention
studies with ET-containing products. The
antioxidant and anticarcinogenic effects of
dietary ETs and EA should be considered in the
gastrointestinal tract whereas the study of
potential systemic activities should be focused on
the bioavailable urolithin B derivatives.
Publication Types:
PMID: 15656654 [PubMed - indexed for MEDLINE]
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Chemoprotection against N-nitrosomethylbenzylamine-induced
mutation in the rat esophagus.
de Boer JG,
Yang H,
Holcroft J,
Skov K.
Centre for Biomedical Research, University of
Victoria, Victoria BC, Canada. jdboer@uvic.ca
Prevention of esophageal cancer may be possible
through dietary modification or supplementation.
In this study we have investigated the mutation
preventive properties of ellagic acid, green tea,
and diallyl sulfide (DAS) against the mutagenicity
of the nitrosamine N-nitrosomethylbenzylamine (NMBA)
in the esophagus of the rat. In addition, the
effect of the consumption of ethanol on the
mutagenicity of NMBA was examined. NMBA is
specific in inducing tumors in the rat esophagus
and has been used in many studies investigating
the mechanism and the prevention of this cancer.
We found that the type of mutations induced by two
2-mg/kg subcutaneous injections of NMBA in the
lacI gene of "Big Blue" rats is consistent with
that found previously for nitrosamines in other
systems and consists of G:C-->A:T transitions. We
report that the addition of ellagic acid to the
feed, replacing drinking water with green tea, and
gavage with DAS significantly reduced the
mutagenicity of NMBA. In contrast, the addition of
5% ethanol to the drinking water increased the
mutagenicity of NMBA. This is consistent with
findings that these compounds modulate NMBA-induced
carcinogenesis in the rat.
PMID: 15623463 [PubMed - indexed for MEDLINE]
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In vitro anti-proliferative
activities of ellagic acid.
Losso JN,
Bansode RR,
Trappey A 2nd,
Bawadi HA,
Truax R.
Department of Food Science, Louisiana State
University, Agricultural Center, Baton Rouge, LA
70803, USA. jlosso@lsu.edu
The potential cytotoxic and anti-proliferative
activities of ellagic acid (a naturally occurring
bioactive compound in berries, grapes, and nuts)
was evaluated using human umbilical vein
endothelial cells (HUVEC), normal human lung
fibroblast cells HEL 299, Caco-2 colon, MCF-7
breast, Hs 578T breast, and DU 145 human prostatic
cancer cells. Ellagic acid at concentration in the
range 10-100 micromol/L did not affect the
viability of normal fibroblast cells during a
24-hour incubation. An increase in adenosine
triphosphate (ATP) bioluminescence of
approximately 18-21% was observed in normal cells
incubated with ellagic acid. In contrast, ellagic
acid at 1-100 micromol/L dose-dependently
inhibited HUVEC tube formation and proliferation
on a reconstituted extracellular matrix and showed
strong anti-proliferative activity against the
colon, breast, and prostatic cancer cell lines
investigated. The most sensitive cells were the
Caco-2, and the most resistant were the breast
cancer cells. Ellagic acid induced cancer cell
death by apoptosis as shown by the microscopic
examination of cell gross morphology. Ellagic acid
induced reduced cancer cell viability as shown by
decreased ATP levels of the cancer cells. After 24
hours incubation of 100 micromol/L of ellagic acid
with Caco-2, MCF-7, Hs 578T, and DU 145 cancer
cells, ellagic acid suppressed fetal bovine serum
(FBS) stimulation of cell migration. The apoptosis
induction was accompanied by a decreased in the
levels of pro-matrix metalloproteinase-2
(pro-MMP-2 or gelatinase A), pro-matrix
metalloproteinase-9 (pro-MMP-9 or gelatinase B),
and vascular endothelial growth factor (VEGF(165))
in conditioned media. The results suggest that
ellagic acid expressed a selective cytotoxicity
and anti-proliferative activity, and induced
apoptosis in Caco-2, MCF-7, Hs 578T, and DU 145
cancer cells without any toxic effect on the
viability of normal human lung fibroblast cells.
It was also observed that the mechanism of
apoptosis induction in ellagic acid-treated cancer
cells was associated with decreased ATP
production, which is crucial for the viability of
cancer cells.
Publication Types:
PMID: 15590271 [PubMed - indexed for MEDLINE]
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Pomegranate fruit extract
modulates UV-B-mediated phosphorylation of mitogen-activated
protein kinases and activation of nuclear factor
kappa B in normal human epidermal keratinocytes
paragraph sign.
Afaq F,
Malik A,
Syed D,
Maes D,
Matsui MS,
Mukhtar H.
Department of Dermatology, University of
Wisconsin, 1300 University Avenue, Madison, WI
53706, USA.
Excessive exposure of solar ultraviolet (UV)
radiation, particularly its UV-B component, to
humans causes many adverse effects that include
erythema, hyperplasia, hyperpigmentation,
immunosuppression, photoaging and skin cancer. In
recent years, there is increasing use of botanical
agents in skin care products. Pomegranate derived
from the tree Punica granatum contains
anthocyanins (such as delphinidin, cyanidin and
pelargonidin) and hydrolyzable tannins (such as
punicalin, pedunculagin, punicalagin, gallagic and
ellagic acid esters of glucose) and possesses
strong antioxidant and anti-inflammatory
properties. Recently, we have shown that
pomegranate fruit extract (PFE) possesses
antitumor promoting effects in a mouse model of
chemical carcinogenesis. To begin to establish the
effect of PFE for humans in this study, we
determined its effect on UV-B-induced adverse
effects in normal human epidermal keratinocytes (NHEK).
We first assessed the effect of PFE on
UV-B-mediated phosphorylation of mitogen-activated
protein kinases (MAPK) pathway in NHEK. Immunoblot
analysis demonstrated that the treatment of NHEK
with PFE (10-40 microg/mL) for 24 h before UV-B
(40 mJ/cm(2)) exposure dose dependently inhibited
UV-B-mediated phosphorylation of ERKl/2, JNK1/2
and p38 protein. We also observed that PFE (20
microg/mL) inhibited UV-B-mediated phosphorylation
of MAPK in a time-dependent manner. Furthermore,
in dose- and time-dependent studies, we evaluated
the effect of PFE on UV-B-mediated activation of
nuclear factor kappa B (NF-kappaB) pathway. Using
Western blot analysis, we found that PFE treatment
of NHEK resulted in a dose- and time-dependent
inhibition of UV-B-mediated degradation and
phosphorylation of IkappaBalpha and activation of
IKKalpha. Using immunoblot analysis, enzyme-linked
immunosorbent assay and electrophoretic mobility
shift assay, we found that PFE treatment to NHEK
resulted in a dose- and time-dependent inhibition
of UV-B-mediated nuclear translocation and
phosphorylation of NF-kappaB/p65 at Ser(536).
Taken together, our data shows that PFE protects
against the adverse effects of UV-B radiation by
inhibiting UV-B-induced modulations of NF-kappaB
and MAPK pathways and provides a molecular basis
for the photochemopreventive effects of PFE.
PMID: 15493960 [PubMed - indexed for MEDLINE]
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Role of chemopreventive agents
in cancer therapy.
Dorai T,
Aggarwal BB.
Comprehensive Cancer Center, Our Lady of Mercy
Medical Center, New York Medical College, Bronx,
NY 10466, USA.
Tumorigenesis or carcinogenesis is a multi-step
process that is induced primarily by carcinogens
leading to the development of cancer. Extensive
research in the last few years has revealed that
regular consumption of certain fruits and
vegetables can reduce the risk of acquiring
specific cancers. Phytochemicals derived from such
fruits and vegetables, referred to as
chemopreventive agents include genistein,
resveratrol, diallyl sulfide, S-allyl cysteine,
allicin, lycopene, capsaicin, curcumin,
6-gingerol, ellagic acid, ursolic acid, silymarin,
anethol, catechins and eugenol. Because these
agents have been shown to suppress cancer cell
proliferation, inhibit growth factor signaling
pathways, induce apoptosis, inhibit NF-kappaB,
AP-1 and JAK-STAT activation pathways, inhibit
angiogenesis, suppress the expression of
anti-apoptotic proteins, inhibit cyclooxygenase-2,
they may have untapped therapeutic value. These
chemopreventive agents also have very recently
been found to reverse chemoresistance and
radioresistance in patients undergoing cancer
treatment. Thus, these chemopreventive agents have
potential to be used as adjuncts to current cancer
therapies.
Publication Types:
PMID: 15488631 [PubMed - indexed for MEDLINE]
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From chemoprevention to
chemotherapy: common targets and common goals.
Aggarwal BB,
Takada Y,
Oommen OV.
The University of Texas M.D. Anderson Cancer
Center, Cytokine Research Section, Department of
Experimental Therapeutics, PO Box 143, 1515
Holcombe Boulevard, Houston, Texas 77030, USA.
aggarwal@mdanderson.org
Three decades of research have revealed that
cancer is easier to prevent than to treat and that
consumption of certain fruits and vegetables can
reduce the risk of cancer. Whereas chemotherapy is
designed to destroy cancer after it appears,
chemoprevention involves the abrogation or delay
in the onset of cancer. Regardless of whether a
chemopreventive or chemotherapeutic approach is
taken, cancer is a multifactorial disease that
requires modulation of multiple pathways and
multiple targets. Various molecular targets of
chemoprevention are also relevant to the therapy
of cancer. These targets include the activation of
apoptosis; suppression of growth factor expression
or signalling; downregulation of antiapoptotic
proteins; suppression of
phosphatidylinositol-3'-kinase/Akt, NF-kappaB,
Janus kinase-signal transducer and activator of
transcription and activator protein-1 signalling
pathways; and downregulation of angiogenesis
through inhibition of vascular endothelial growth
factor expression, cyclooxygenase-2, matrix
metalloproteinase-9, urokinase-type plasminogen
activator, adhesion molecules and cyclin D1.
Pharmacologically safe phytochemicals that have
been identified from plants or their variant forms
can modulate these molecular targets. These
phytochemicals include genistein, resveratrol,
dially sulfide, S-ally cysteine, allicin, lycopene,
capsaicin, curcumin, 6-gingerol, ellagic acid,
ursolic acid, betulinic acid, flavopiridol,
silymarin, anethol, catechins and eugenol. Recent
work has shown that these phytochemicals also can
reverse chemoresistance and radioresistance.
Because of their pharmacological safety, these
agents can be used alone to prevent cancer and in
combination with chemotherapy to treat cancer.
Publication Types:
PMID: 15461561 [PubMed - indexed for MEDLINE]
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Inhibition of the rat breast
cytosolic bioactivation of ethanol to acetaldehyde
by some plant polyphenols and folic acid.
Maciel ME,
Castro GD,
Castro JA.
Centro de Investigaciones Toxicológicas, Buenos
Aires, Argentina.
There is a well-established association between
alcohol consumption and breast cancer risk. About
4% of the breast cancers in developed countries
are estimated to be attributable to drinking
alcohol. The mechanism of tumor promotion by
alcohol remains unknown. Recent studies from our
laboratory and others showed the ability of
mammary tissue to bioactivate ethanol to
mutagenic/carcinogenic acetaldehyde and free
radicals. Xanthine oxidoreductase (XOR) is an
enzyme involved in those biotransformation
processes. In the present study, we provide
evidence of the ability of different natural
polyphenols and of folic acid derivatives to
inhibit the biotransformation of alcohol to
acetaldehyde by rat breast cytosolic XOR. Folic
acid and dihydrofolic acid, at concentrations of
10 microM, inhibited 100% and 84%, respectively,
of the cytosolic acetaldehyde formation.
Thirty-five polyphenols were tested in these
initial experiments: ellagic acid, myricetin,
quercetin, luteolin, and apigenin inhibited 79-95%
at 10 microM concentrations. The remaining
polyphenols were either less potent or
noninhibitory of acetaldehyde formation at similar
concentrations in these screening tests. Results
are relevant to the known preventive effects of
folic acid against alcohol-induced breast cancer
and to their potential preventive actions if added
to foods or alcoholic beverages.
Publication Types:
PMID: 15456641 [PubMed - indexed for MEDLINE]
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Prevention and repair of DNA
damage by selected phytochemicals as measured by
single cell gel electrophoresis.
Chakraborty S,
Roy M,
Bhattacharya RK.
Department of Environmental Carcinogenesis and
Toxicology, Chittaranjan National Cancer
Institute, Kolkata, India.
We assessed the ability of some natural
products--namely, curcumin, resveratrol,
indole-3-carbinol, and ellagic acid--to modify the
DNA damaging ability of the alkylating carcinogen
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in
cultured Chinese hamster lung fibroblast cells (CH
V-79). MNNG produced DNA single strand breaks in a
dose- and time-dependent manner, as observed by
increase in the tail moments of the comet, when
the cells were subjected to alkaline single cell
gel electrophoresis. When the cells were treated
in the presence of each of the natural compounds,
the DNA damage caused by MNNG was considerably
reduced. This effect was found to be dose related.
Preincubation of cells with each of these
compounds individually afforded significant
protection to DNA against damage caused by
subsequent treatment with MNNG, indicating a true
chemopreventive role of these substances. The most
remarkable aspect of the present study was that
all four compounds helped in the recovery of DNA
damage by accelerating DNA repair efficiency in
the damaged cells. This was further substantiated
by the observation on unscheduled DNA synthesis.
Our results suggest that these agents are
chemopreventive by virtue of their ability to
protect DNA as well as to induce DNA repair.
PMID: 15312044 [PubMed - indexed for MEDLINE]
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Antimutagenic/antioxidant
activity of green tea components and related
compounds.
Pillai SP,
Mitscher LA,
Menon SR,
Pillai CA,
Shankel DM.
Department of Medicinal Chemistry and Molecular
Bioscience, University of Kansas, Lawrence, KS
66045, USA.
The ability of green tea components and other
antioxidant compounds to function as antimutagens/antioxidants
has been well established, and their role in
cancer prevention is supported by numerous
epidemiological studies. We have utilized modified
Ames tests, superoxide scavenging assays, and
assays for protection against DNA scissions to
compare and contrast the protective effects of
various teas and commercial and
laboratory-isolated tea components to those
produced by compounds such as resveratrol,
selenium, curcumin, vitamins C and E, quercetin
dihydrate, sulforaphane, ellagic acid dihydrate,
glutathione reduced, trolox, butylated
hydroxanisole (BHA), butylated hydroxytoluene (BHT),
and N-acetyl-L-cysteine (NAC). In Ames tests,
employing hydrogen peroxide as a mutagen,
epigallocatechin gallate (EGCG) produced the
highest level of protection of all antioxidants
tested. Measurement of protection against DNA
scissions produced results that again showed that
EGCG produced the strongest protective effects. In
scavenging assays using a xanthine-xanthine
oxidase (enzymatic system), epicatechin gallate (ECG)
showed the highest scavenging potential. In a
nonenzymatic (phenazine methosulfate-NADH)
oxidizing system, EGCG once again showed the
strongest effects. The implications of these and
similar results are discussed in relation to
cancer prevention and prevention of
drug/antibiotic resistance.
Publication Types:
PMID: 15281227 [PubMed - indexed for MEDLINE]
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Potential impact of
strawberries on human health: a review of the
science.
Hannum SM.
Nutritional Sciences, University of Illinois, USA.
Epidemiological studies have noted a consistent
association between the consumption of diets rich
in fruits and vegetables and a lower risk for
chronic diseases including cancer and
cardiovascular disease. There is accumulating
evidence that much of the health-promoting
potential of these plant foods may come from
phytochemicals, bioactive compounds not designated
as traditional nutrients. In strawberries, the
most abundant of these are ellagic acid, and
certain flavonoids: anthocyanin, catechin,
quercetin and kaempferol. These compounds in
strawberries have potent antioxidant power.
Antioxidants help lower risk of cardiovascular
events by inhibition of LDL-cholesterol oxidation,
promotion of plaque stability, improved vascular
endothelial function, and decreased tendency for
thrombosis. Furthermore, strawberry extracts have
been shown to inhibit COX enzymes in vitro, which
would modulate the inflammatory process.
Individual compounds in strawberries have
demonstrated anticancer activity in several
different experimental systems, blocking
initiation of carcinogenesis, and suppressing
progression and proliferation of tumors.
Preliminary animal studies have indicated that
diets rich in strawberries may also have the
potential to provide benefits to the aging brain.
Publication Types:
PMID: 15077879 [PubMed - indexed for MEDLINE]
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Intestinal epithelial cell
accumulation of the cancer preventive polyphenol
ellagic acid--extensive binding to protein and
DNA.
Whitley AC,
Stoner GD,
Darby MV,
Walle T.
Department of Cellular 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 many
berries, has been demonstrated to be preventive of
esophageal cancer in animals both at the
initiation and promotion stages. To be able to
extrapolate these findings to humans we have
studied the transcellular absorption and
epithelial cell accumulation of [14C]EA in the
human intestinal Caco-2 cells. The apical
(mucosal) to basolateral (serosal) transcellular
transport of 10 microM [14C]EA was minimal with a
P(app) of only 0.13 x 10(-6)cm/s, which is less
than for the paracellular transport marker
mannitol. In spite of observations of basolateral
to apical efflux, Caco-2 cell uptake studies
showed high accumulation of EA in the cells
(1054+/-136 pmol/mg protein), indicating facile
absorptive transport across the apical membrane.
Surprisingly, as much as 93% of the cellular EA
was irreversibly bound to macromolecules
(982+/-151 pmol/mg protein). To confirm the
irreversible nature of the binding to protein,
Caco-2 cells treated with 10 microM [14C]EA were
subjected to SDS-PAGE analysis. This resulted in
radiolabeled protein bands trapped in the stacking
gel, consistent with [14C]EA-crosslinked proteins.
Treatment of Caco-2 cells with 10 microM [14C]EA
also revealed irreversible binding of EA to
cellular DNA as much as five times higher than for
protein (5020+/-773 pmol/mg DNA). Whereas the
irreversible binding to protein required oxidation
of EA by reactive oxygen species, this did not
seem to be the case with the DNA binding. The avid
irreversible binding to cellular DNA and protein
may be the reason for its highly limited
transcellular absorption. Thus, EA appears to
accumulate selectively in the epithelial cells of
the aerodigestive tract, where its cancer
preventive actions may be displayed.
Publication Types:
PMID: 12963477 [PubMed - indexed for MEDLINE]
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Low concentrations of quercetin
and ellagic acid synergistically influence
proliferation, cytotoxicity and apoptosis in
MOLT-4 human leukemia cells.
Mertens-Talcott SU,
Talcott ST,
Percival SS.
Food Science and Human Nutrition Department,
University of Florida, Gainesville, FL 32611, USA.
Little information is available regarding possible
synergistic or antagonistic biochemical
interactions among polyphenols contained in fruits
and vegetables. Identifying potential interactions
among these compounds may help to define the
efficiency of polyphenol-containing foods in
cancer prevention as related to structure-function
activity of the compounds. The objective of this
study was to investigate interactions between
quercetin and ellagic acid, two polyphenolics that
are present predominantly in small fruits, on cell
death and proliferation-related variables in the
MOLT-4 human leukemia cell line. Assays were
performed to determine cell cycle kinetics,
proliferation, apoptotic DNA-fragmentation and
caspase-3-activity after 12, 24 and 48 h. Ellagic
acid significantly potentiated the effects of
quercetin (at 5 and 10 micro mol/L each) in the
reduction of proliferation and viability and the
induction of apoptosis. Significant alterations in
cell cycle kinetics were also observed. The
synergy was confirmed by an isobolographic
analysis of the cell proliferation data. The
interaction of ellagic acid and quercetin
demonstrated an enhanced anticarcinogenic
potential of polyphenol combinations, which was
not based solely on the additive effect of
individual compounds, but rather on synergistic
biochemical interactions.
Publication Types:
PMID: 12888656 [PubMed - indexed for MEDLINE]
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Induction of rat hepatic and
intestinal UDP-glucuronosyltransferases by
naturally occurring dietary anticarcinogens.
van der Logt EM,
Roelofs HM,
Nagengast FM,
Peters WH.
Department of Gastroenterology, University Medical
Centre St Radboud, PO Box 9101, 6500 HB Nijmegen,
The Netherlands.
Gastrointestinal tumours are among the most common
malignancies in Western society, the majority of
which are associated with dietary and lifestyle
factors. Many dietary or lifestyle factors have
been identified which may have toxic or
carcinogenic properties. However, several dietary
compounds also able to reduce gastrointestinal
cancer rates in both humans and animals have been
characterized. Though the exact mechanism leading
to the anticarcinogenic action of these compounds
is not fully known, it has been demonstrated that
this chemopreventive capacity may be due to
elevation of the glutathione S-transferase
detoxification enzymes. Here we have investigated
the effect of several anticarcinogens on the
gastrointestinal UDP-glucuronosyltransferase (UGT)
enzymes. Diets of male Wistar rats were
supplemented with ellagic acid, ferulic acid,
Brussels sprouts, quercetin, alpha-angelicalactone,
tannic acid, coumarin, fumaric acid, curcumin and
flavone, separately, and combinations of alpha-angelicalactone
and flavone. Hepatic and intestinal (proximal, mid
and distal small intestine and colon) UGT enzyme
activities were quantified using 4-nitrophenol and
4-methylumbelliferone as substrates. All
anticarcinogens tested increased UGT enzyme
activity with both substrates, at one at least of
the five different sites investigated. alpha-Angelicalactone,
coumarin and curcumin showed enhanced UGT enzyme
activities at all five sites. Both small and large
intestinal UGT enzyme activities were increased by
quercetin, alpha-angelicalactone, coumarin,
curcumin and flavone. Except for tannic acid, all
agents induced hepatic UGT enzyme activity.
Furthermore, dietary administration of alpha-angelicalactone
and flavone, given individually or in combination,
enhanced the UGT detoxification system in the
liver and, to a lesser extent, in intestine. In
conclusion, induction of gastrointestinal UGT
enzyme activities after consumption of dietary
anticarcinogens may contribute to a better
detoxification of potentially carcinogenic
compounds and subsequently to the prevention of
gastrointestinal cancer.
Publication Types:
PMID: 12869420 [PubMed - indexed for MEDLINE]
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Isolation and synthesis of a
new bioactive ellagic acid derivative from
Combretum yunnanensis.
Asami Y,
Ogura T,
Otake N,
Nishimura T,
Xinsheng Y,
Sakurai T,
Nagasawa H,
Sakuda S,
Tatsuta K.
Department of Biosciences, School of Science and
Technology, Teikyo University, 1-1 Toyosatodai,
Utsunomiya 320-8551, Japan.
A new ellagic acid derivative (1) was isolated
from the branches of Combretum yunnanensis, and
its structure was assigned as 4-(4'
'-O-acetyl-alpha-rhamnopyranosyl)ellagic acid by
analysis of its spectral data. Total synthesis of
1 was achieved by the glycosylation of
3,3'-di-O-benzylellagic acid (5) with
4-O-acetyl-2,3-di-O-benzyl-l-rhamnose (4) as a key
reaction, and the absolute configuration of 1 was
determined. Compound 1 showed weak inhibitory
activity against the growth of various tumor cells
and inhibited HIV-1 protease.
Publication Types:
PMID: 12762821 [PubMed - indexed for MEDLINE]
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