Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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101:
Cancer Lett. 1995 Aug
16;95(1-2):221-5.
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Inhibition of lung metastasis in mice
induced by B16F10 melanoma cells by
polyphenolic compounds.
Menon LG,
Kuttan R,
Kuttan G.
Amala Cancer Research Centre, Thrissur,
Kerala, India.
Several polyphenolic compounds were tested
for the inhibition of lung metastasis
induced by B16F10 melanoma cells in mice.
Oral administration of polyphenols such as
curcumin and catechin at concentrations of
200 nmol/kg body weight were found to
inhibit the lung metastasis maximally as
seen by the reduction in the number of lung
tumor nodules (80%). Other polyphenols which
inhibited the lung tumor nodule formation
were rutin (71.2%), epicatechin (61%),
naringin (27.2%) and naringenin (26.1%). The
polyphenols which did not inhibit lung tumor
nodule formation were quercetin, morin and
ellagic acid. Consequent to the inhibition
of the lung tumor nodules, the life span of
animals treated with polyphenols was also
found to be increased. Curcumin (143.85%),
catechin (80.81%) and rutin (63.59%) had
maximal increase in life span. The results
indicate a possible use of these compounds
in arresting the metastatic growth of tumor
cells.
Publication Types:
PMID: 7656234 [PubMed - indexed for MEDLINE]
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Modulating effects of ellagic acid,
vanillin and quercetin in a rat medium term
multi-organ carcinogenesis model.
Akagi K,
Hirose M,
Hoshiya T,
Mizoguchi Y,
Ito N,
Shirai T.
First Department of Pathology, Nagoya City
University, Medical School, Japan.
Effects of dietary supplementation with the
antioxidants ellagic acid, quercetin and
vanillin were examined using a medium term
multi-organ carcinogenesis model in rats.
Groups of 10-15 male F344 rats were given
i.p. injections of diethylnitrosamine (DEN,
100 mg/kg body wt.) and N-methylnitrosourea
(MNU, 20 mg/kg body wt), s.c. injections of
1,2-dimethylhydrazine (DMH, 40 mg/kg body
wt.), together with 0.05% N-butyl-N-(4-
hydroxybutyl)nitrosamine (BBN) and 0.1%
2,2'-dihydroxy-di-n-propylnitrosamine (DHPN),
both in the drinking water, for a total
multiple initiation period of 4 weeks (DMBDD)
treatment). Ellagic acid, quercetin or
vanillin, each at a dose of 1% each in the
diet were administered from 1 day before and
throughout the carcinogen exposure period,
or after completion of the initiation
regimen. All surviving animals were
sacrificed at the end of week 36, and major
organs were examined histopathologically. In
the small intestine, significant reductions
in the incidence and number of tumors
(adenomas and carcinomas) were observed in
the groups administered ellagic acid during
(8%, 0.08 +/- 0.29) or after (8%, 0.08 +/-
0.29) DMBDD treatment, and those receiving
quercetin after DMBDD treatment (0%)
compared to the control value (57%, 1.07 +/-
1.21). Although the incidences were not
statistically significant, slightly
decreased numbers of small intestinal tumors
were found in the groups receiving vanillin
during (0.33 +/- 0.72), or after (0.40 +/-
0.83) DMBDD treatment. The incidence of
large intestinal carcinomas in the group
treated with vanillin during DMBDD treatment
was significantly higher (73%) than the
control value (21%). These results indicated
that while ellagic acid and quercetin
exerted potent chemopreventive action in
both the initiation and promotion stages in
the present experimental system, their
beneficial effects were restricted to the
small intestine. Since small intestinal
carcinomas are very infrequent in humans,
the advantages of these phenolic compounds
for human application as chemopreventors
should not be overestimated.
Publication Types:
PMID: 7621439 [PubMed - indexed for MEDLINE]
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Effects of dietary phenethyl
isothiocyanate, ellagic acid, sulindac and
calcium on the induction and progression of
N-nitrosomethylbenzylamine-induced
esophageal carcinogenesis in rats.
Siglin JC,
Barch DH,
Stoner GD.
Department of Pathology, Medical College of
Ohio, Toledo 43699-0008, USA.
The potential inhibitory effects of
phenethyl isothiocyanate (PEITC), ellagic
acid (EA), sulindac and supplemental dietary
calcium (SDC) on N-nitrosomethylbenzylamine
(NMBA)-induced esophageal carcinogenesis
were evaluated in rats utilizing an
abbreviated (5 week) NMBA treatment protocol
which allowed administration of the putative
inhibitors throughout the experiment (i.e.
beginning 2 weeks prior to NMBA treatment)
or following completion of NMBA dosing only.
PEITC at 500 p.p.m. significantly inhibited
tumor incidence and multiplicity when given
before and during, but not following, NMBA
treatment. Neither sulindac at 125 p.p.m.
nor SDC (2% versus 0.5% in control diet)
inhibited tumor development when given
during or following NMBA treatment. EA,
which was administered only following NMBA
treatment, significantly reduced the
incidence (66.7% versus 100% in NMBA
controls), but not the multiplicity, of
esophageal tumors at the high-dose (4000
p.p.m.) level. Together these findings
indicate that: (i) PEITC selectively
inhibits the induction but not the
subsequent progression of NMBA-induced
esophageal tumors; (ii) EA may repress
esophageal tumor development when
administered following NMBA treatment; (iii)
at the doses administered, neither sulindac
nor SDC possess significant inhibitory
activity against NMBA-induced esophageal
carcinogenesis in the rat.
Publication Types:
PMID: 7767971 [PubMed - indexed for MEDLINE]
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Chemoprevention of
2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine
(PhIP)-induced mammary gland carcinogenesis
by antioxidants in F344 female rats.
Hirose M,
Akagi K,
Hasegawa R,
Yaono M,
Satoh T,
Hara Y,
Wakabayashi K,
Ito N.
First Department of Pathology, Nagoya City
University, Medical School, Japan.
Chemopreventive effects of the antioxidants
1-O-hexyl-2,3,5- trimethylhydroquinone (HTHQ),
3-O-ethylascorbic acid (EAsA),
3-O-dodecylcarbomethylascorbic acid (DAsA),
green tea catechins (GTC) and ellagic acid
on 2-amino-1-methyl-6-
phenylimidazo[4,5-b]pyridine (PhIP)-induced
mammary carcinogenesis were examined in
female F344 rats. Groups of 20-21 6-week-old
rats were maintained on a powdered diet
containing 0.02% PhIP alone, PhIP together
with 0.5% HTHQ, 1% EAsA, 1% DAsA, 1% GTC or
0.1% ellagic acid, these antioxidants alone
or basal diet alone without supplement for
52 weeks. The survival rates of PhIP plus
antioxidant groups at the end of the
experiment were higher than that of the PhIP
alone group. Sequential observation of
palpable mammary tumors demonstrated only
one tumor by week 52 in the PhIP plus HTHQ
group, whereas 40% of the rats receiving
PhIP alone had tumors by this time point.
The final incidence of mammary
adenocarcinomas was significantly decreased
in the PhIP plus HTHQ group (4.8%, P < 0.01)
as compared to the PhIP alone value (40%).
Although statistically not significant,
incidences of adenocarcinomas in the other
antioxidant-treated groups (23.8-28.6%) were
also lower than in the PhIP alone group.
Furthermore, the incidence of large
intestinal tumors in the PhIP plus HTHQ
group (0%) showed a tendency to decrease
relative to the PhIP alone group (16.7%).
These results indicate that antioxidants,
particularly HTHQ, exert a potent
chemopreventive action against PhIP-induced
carcinogenesis.
Publication Types:
PMID: 7859351 [PubMed - indexed for MEDLINE]
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Polyphenols as cancer chemopreventive
agents.
Stoner GD,
Mukhtar H.
Department of Preventive Medicine, Ohio
State University, Columbus 43210, USA.
This article summarizes available data on
the chemopreventive efficacies of tea
polyphenols, curcumin and ellagic acid in
various model systems. Emphasis is placed
upon the anticarcinogenic activity of these
polyphenols and their proposed mechanism(s)
of action. Tea is grown in about 30
countries and, next to water, is the most
widely consumed beverage in the world. Tea
is manufactured as either green, black, or
oolong; black tea represents approximately
80% of tea products. Epidemiological
studies, though inconclusive, suggest a
protective effect of tea consumption on
human cancer. Experimental studies of the
antimutagenic and anticarcinogenic effects
of tea have been conducted principally with
green tea polyphenols (GTPs). GTPs exhibit
antimutagenic activity in vitro, and they
inhibit carcinogen-induced skin, lung,
forestomach, esophagus, duodenum and colon
tumors in rodents. In addition, GTPs inhibit
TPA-induced skin tumor promotion in mice.
Although several GTPs possess
anticarcinogenic activity, the most active
is (-)-epigallocatechin-3-gallate (EGCG),
the major constituent in the GTP fraction.
Several mechanisms appear to be responsible
for the tumor-inhibitory properties of GTPs,
including enhancement of antioxidant
(glutathione peroxidase, catalase and
quinone reductase) and phase II
(glutathione-S-transferase) enzyme
activities; inhibition of chemically induced
lipid peroxidation; inhibition of
irradiation- and TPA-induced epidermal
ornithine decarboxylase (ODC) and
cyclooxygenase activities; inhibition of
protein kinase C and cellular proliferation;
antiinflammatory activity; and enhancement
of gap junction intercellular communication.
Curcumin is the yellow coloring agent in the
spice tumeric. It exhibits antimutagenic
activity in the Ames Salmonella test and has
anticarcinogenic activity, inhibiting
chemically induced preneoplastic lesions in
the breast and colon and neoplastic lesions
in the skin, forestomach, duodenum and colon
of rodents. In addition, curcumin inhibits
TPA-induced skin tumor promotion in mice.
The mechanisms for the anticarcinogenic
effects of curcumin are similar to those of
the GTPs. Curcumin enhances glutathione
content and glutathione-S-transferase
activity in liver; and it inhibits lipid
peroxidation and arachidonic acid metabolism
in mouse skin, protein kinase C activity in
TPA-treated NIH 3T3 cells, chemically
induced ODC and tyrosine protein kinase
activities in rat colon, and
8-hydroxyguanosine formation in mouse
fibroblasts. Ellagic acid is a polyphenol
found abundantly in various fruits, nuts and
vegetables. Ellagic acid is active in
antimutagenesis assays, and has been shown
to inhibit chemically induced cancer in the
lung, liver, skin and esophagus of rodents,
and TPA-induced tumor promotion in mouse
skin.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
PMID: 8538195 [PubMed - indexed for MEDLINE]
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Chemopreventive effects of beta-carotene,
alpha-tocopherol and five naturally
occurring antioxidants on initiation of
hepatocarcinogenesis by
2-amino-3-methylimidazo[4,5-f]quinoline in
the rat.
Tsuda H,
Uehara N,
Iwahori Y,
Asamoto M,
Iigo M,
Nagao M,
Matsumoto K,
Ito M,
Hirono I.
Chemotherapy Division, National Cancer
Center Research Institute, Tokyo.
Inhibitory effects of naturally occurring
antioxidants on the initiation stage of
hepatocarcinogenesis were studied. Group 1
rats were given a diet containing
beta-carotene (beta-CT, 0.02%), alpha-tocopherol
(alpha-TP, 1.5%), glutathione (GLT, 5%),
vanillin (VNL, 1%), quercetin (QCT, 1%) or
ellagic acid (ELA, 1%), or 3 doses of
diallyl sulfide (DAS, 200 mg/kg, i.g.) over
an 8-day period. On day 7, the animals
received a single dose of
2-amino-3-methylimidazo[4,5-f] quinoline
(IQ, 100 mg/kg, i.g.), 12 h after two-thirds
partial hepatectomy for initiation and 2
weeks thereafter, were placed on promotion
regimen comprising phenobarbital (0.05% in
diet) and a single dose of D-galactosamine
(100 mg/kg, i.p.). Groups 2 and 3 were
treated as described for Group 1, but
without test material or IQ, respectively.
Survivors were killed at week 11 and
antioxidant influence was assessed by
comparing values for preneoplastic
glutathione S-transferase placental
form-positive (GST-P+) foci between Groups 1
and 2. All lesions larger than 70 microns in
diameter consisting of approximately 5 cells
in cross section were counted. Numbers of
GST-P+ foci/cm2 in Group 1 were: beta-CT,
7.99; alpha-TP, 8.21; GLT, 9.71; DAS, 10.37;
VNL, 10.57; QCT, 11.1; ELA, 12.5 (n =
11-15). All, except ELA, showed a
significant decrease as compared with the
Group 2 value of 14.54 (n = 15). Only
beta-CT showed a significant decrease for
the area value. This is the first report to
show that beta-CT, alpha-TP, GLT, DAS, VNL,
QCT exert inhibitory effects on initiation
of hepatocarcinogenesis by the food
carcinogen IQ, suggesting that these
antioxidants might find application as
chemopreventive agents. Furthermore, the
current protocol proved practical for the
assessment of chemopreventive agents within
11 weeks, a relatively short period.
Publication Types:
PMID: 7852184 [PubMed - indexed for MEDLINE]
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Ellagic acid induces NAD(P)H:quinone
reductase through activation of the
antioxidant responsive element of the rat
NAD(P)H:quinone reductase gene.
Barch DH,
Rundhaugen LM.
Department of Medicine, Lakeside Veterans
Affairs Medical Center, Chicago, IL.
Induction of cellular detoxification enzymes
can increase detoxification of carcinogens
and reduce carcinogen-induced mutagenesis
and tumorigenesis. To determine if the
dietary anticarcinogen ellagic acid induced
enzymes which detoxify xenobiotics and
carcinogens, we examined the effect of
ellagic acid on the expression of the phase
II detoxification enzyme NAD(P)H:quinone
reductase (QR). QR is induced by xenobiotics
and antioxidants interacting with the
xenobiotic responsive and antioxidant
responsive elements of the 5' regulatory
region of the QR gene. Ellagic acid is
structurally related to the antioxidants
which induce QR and we proposed that ellagic
acid would induce QR expression through
activation of the antioxidant responsive
element of the QR gene. Rats fed ellagic
acid demonstrated a 9-fold increase in
hepatic and a 2-fold increase in pulmonary
QR activity, associated with an 8-fold
increase in hepatic QR mRNA. To determine if
this increase in QR mRNA was due to
activation of the antioxidant responsive
element, transient transfection studies were
performed with plasmid constructs containing
various portions of the 5' regulatory region
of the rat QR gene. These transfection
studies confirmed that ellagic acid induces
transcription of the QR gene and
demonstrated that this induction is mediated
through the antioxidant responsive element
of the QR gene.
Publication Types:
PMID: 7522986 [PubMed - indexed for MEDLINE]
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Chemopreventive drug development:
perspectives and progress.
Kelloff GJ,
Boone CW,
Crowell JA,
Steele VE,
Lubet R,
Sigman CC.
Chemoprevention Investigational Studies
Branch, National Cancer Institute, Bethesda,
Maryland 20892.
Chemoprevention drug development has the
goal of identifying safe and effective
chemopreventive agents for clinical use.
Several distinctive strategies are pursued
in developing chemopreventive agents: (a)
identifying and validating predysplastic and
early dysplastic lesions that can be used
instead of cancers as endpoints for
measuring chemopreventive activity; (b)
identifying and testing candidate agents
based on considerations of mechanisms of
action; (c) evaluating combinations of
agents with potential for maximizing
efficacy and minimizing toxicity; and (d)
applying a systematic methodology for
identifying and ranking candidate agents at
each stage of development to ensure
discovery of the best agents and most
effective use of available resources. This
article discusses 22 drugs and three drug
combinations which have reached an advanced
stage of development as chemopreventive
agents. The first generation of drugs are
the most advanced, now being in Phase II and
Phase III clinical trials. These drugs
include several retinoids [vitamin A,
13-cis-retinoic acid,
all-trans-N-(4-hydroxyphenyl)retinamide],
calcium, beta-carotene, tamoxifen, and
finasteride. The second generation drugs are
those in Phase I clinical trials. From most
to least advanced, these drugs are
2-difluoromethylornithine, sulindac,
piroxicam, oltipraz, N-acetyl-I-cysteine,
aspirin, ibuprofen, carbenoxolone, 18 beta-glycyrrhetinic
acid, and the combination of
2-difluoromethylornithine with piroxicam.
The third generation includes agents with
significant evidence of chemopreventive
activity in animal models. These agents are
now in preclinical toxicity testing. They
are S-allyl-I-cysteine, phenhexyl
isothiocyanate, curcumin, ellagic acid,
fumaric acid, fluasterone, and the
combinations of
all-trans-N-(4-hydroxyphenyl)retinamide with
oltipraz and all-trans-N-(4-hydroxyphenyl)
retinamide with tamoxifen.
Publication Types:
PMID: 8118391 [PubMed - indexed for MEDLINE]
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Chemoprevention of cancer.
Szarka CE,
Grana G,
Engstrom PF.
Division of Population Science, Fox Chase
Cancer Center.
Chemoprevention is a strategy used to block
the development of cancers in human beings.
This emerging field has broad potential for
influencing cancer incidence rates in
defined high-risk groups and the general
population. In this review, we define some
of the mechanisms of carcinogenesis,
describe some of the genetic markers of
carcinogenesis, and list possible biomarkers
that may serve as surrogate end points in
chemoprevention studies. A major component
of this review is a description of the
agents that are currently under
investigation in animal systems or in human
trials. They are grouped according to the
agents that block or suppress mutation, such
as oltipraz, selenium, vitamin C and the
flavones, or according to agents that block
promotion and proliferation, such as
difluoromethylornithine, tamoxifen,
nonsteroidal antiinflammatory drugs, and the
vitamin A derivatives. We describe the
issues that are considered in the design of
chemoprevention trials and in the phase I,
II, and III components of these trials. The
following national trials are discussed: the
Breast Cancer Prevention Trial, which uses
tamoxifen; the Prostate Cancer Prevention
Trial, which uses finasteride; and a Lung
Cancer Prevention Trial, which uses
13-cis-retinoic acid. The review ends with
some insights about future studies in
chemoprevention.
Publication Types:
PMID: 8005001 [PubMed - indexed for MEDLINE]
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Inhibition of
4-nitroquinoline-1-oxide-induced rat tongue
carcinogenesis by the naturally occurring
plant phenolics caffeic, ellagic,
chlorogenic and ferulic acids.
Tanaka T,
Kojima T,
Kawamori T,
Wang A,
Suzui M,
Okamoto K,
Mori H.
1st Department of Pathology, Gifu University
School of Medicine, Japan.
The modifying effects of dietary
administration of the plant phenolic
antioxidants caffeic acid (CA), ellagic acid
(EA), chlorogenic acid (CGA) and ferulic
acid (FA) during the initiation phase on
4-nitroquinoline-1-oxide (4-NQO)-induced
tongue carcinogenesis and on the number and
area of silver-stained nucleolar organizer
region proteins (AgNORs), a new cell
proliferation marker, of the tongue squamous
epithelium were investigated in male F344
rats. Rats were fed the diet containing 500
p.p.m. CA, 400 p.p.m. EA, 250 p.p.m. CGA or
500 p.p.m. FA for 7 weeks. One week after
the commencement of the diets, 4-NQO (20
p.p.m.) was administered in the drinking
water for 5 weeks. Feeding of four phenolic
compounds significantly reduced the
incidences of tongue neoplasms (squamous
cell papilloma and carcinoma) and
preneoplastic lesions (hyperplasia and
dysplasia) by 32 weeks, and rats fed CA or
EA had no tongue neoplasms. The number and
area of AgNORs per nucleus were decreased
significantly by dietary treatment with
these four phenolics. Thus, CA, EA, CGA and
FA inhibited the tongue carcinogenesis
induced by 4-NQO when they were administered
concurrently with the carcinogen. These
results might suggest possible application
of these natural substances for cancer
chemoprevention in tongue in addition to
other tissues (skin, lung, liver and
esophagus).
PMID: 8330344 [PubMed - indexed for MEDLINE]
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Pulmonary carcinogenesis and its
prevention by dietary polyphenolic
compounds.
Castonguay A.
Laboratory of Cancer Etiology and
Chemoprevention, School of Pharmacy, Laval
University, Quebec City, Canada.
The aims of this study were to define the
cumulative exposure of Canadian smokers to
NNK and to characterize the efficacy of
ellagic acid to inhibit lung tumorigenesis
induced by NNK. The sales-weighted average
of NNK deliveries from Canadian cigarettes
was 73.2 ng/cigarette. NNK deliveries were
highly correlated to declared tar values and
were linear with puff volumes between 20 and
50 ml. Ellagic acid inhibited lung
tumorigenesis induced by NNK in A/J mice.
This inhibition was related to the logarithm
of the dose of ellagic acid added to the
diet. The biodistribution of ellagic acid
was studied in mice gavaged with ellagic
acid. Pulmonary levels of ellagic acid were
directly proportional to the dose of ellagic
acid between 0.2 and 2.0 mmol/kg b.w.
Publication Types:
PMID: 8512246 [PubMed - indexed for MEDLINE]
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Lung tumors in strain A mice: application
for studies in cancer chemoprevention.
Stoner GD,
Adam-Rodwell G,
Morse MA.
Ohio State University, Department of
Preventive Medicine, Arthur G. James Cancer
Hospital and Research Institute, Columbus
43210.
Strain A mice develop a high incidence of
spontaneous lung tumors during their
lifetime. These tumors may be found in some
animals as early as 3 to 4 weeks of age,
increasing to nearly 100% by 24 months of
age. The strain A mouse is also highly
susceptible to the induction of lung tumors
by several classes of chemical carcinogens
and has been used extensively as a mouse
lung tumor bioassay for assessing the
carcinogenic activity of a variety of
chemicals. In addition to its use in
carcinogen detection, the strain A mouse
lung tumor model has been employed
extensively for the identification of
inhibitors of chemical carcinogenesis. A
number of chemopreventive agents including
beta-naphthoflavone, butylated
hydroxyanisole, ellagic acid, phenethyl
isothiocyanate, phenylpropyl isothiocyanate,
phenylbutyl isothiocyanate, phenylhexyl
isothiocyanate, indole-3-carbinol, etc.,
have been shown to inhibit chemically
induced lung tumors in strain A mice. In
most instances, inhibition of lung
tumorigenesis has been correlated with
effects of the chemopreventive agent on the
metabolic activation and/or detoxification
of carcinogens. To date, no chemopreventive
agent has been shown to inhibit lung
tumorigenesis in strain A mice when
administered after the carcinogen, i.e.,
during the promotion/progression stages of
tumor development. Efforts should be made to
develop a standardized protocol in strain A
mice for evaluating chemopreventive agents
as inhibitors of both the initiation and
progression stages of lung tumor
development.
PMID: 8412213 [PubMed - indexed for MEDLINE]
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Synthesis of ellagic acid O-alkyl
derivatives and isolation of ellagic acid as
a tetrahexanoyl derivative from Fragaria
ananassa.
Heur YH,
Zeng W,
Stoner GD,
Nemeth GA,
Hilton B.
Department of Pathology, Medical College of
Ohio, Toledo 43614.
Ellagic acid [1] is a gallic acid dimer that
occurs in plants, fruits, and nuts, either
in its free form, or in a series of
ellagitannins, or as a glucoside. It has
been shown to inhibit cancer induced by
several types of chemical carcinogens
including polycyclic aromatic hydrocarbons,
N-nitrosamines, aflatoxin, and aromatic
amines. It has been extracted from a number
of fruits, including strawberries; however,
its presence in the extracts was determined
only by hplc connected with a diode array
detector. In the present report, ellagic
acid was isolated as a tetrahexanoyl
derivative 2 from Fragaria ananassa and
identified by 13C and 1H nmr and ms. The
13C-nmr shifts of the aromatic carbons
adjacent to a hexanoyloxy group were
assigned using two new synthetic model
compounds:
3,3'-dihexanoyloxydiphenic-2,2',6,6'-dilactone
[3] and
4,4'-dihexanoyloxydiphenic-2,2',6,6'-dilactone
[4]. Two new derivatives of ellagic acid
[1],3,3'-di-beta-D-glucopyranosylellagic
acid decaacetate [5] and
3,3'-di-n-octyl-4,4'-dihexanoylellagic acid
[7], were also synthesized. Both derivatives
were less effective as inhibitors of
benzo[a]pyrene tumorigenesis in the lungs of
strain A/J mice than ellagic acid.
Publication Types:
PMID: 1453178 [PubMed - indexed for MEDLINE]
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Reversal of aflatoxin induced liver
damage by turmeric and curcumin.
Soni KB,
Rajan A,
Kuttan R.
Amala Cancer Research Centre, Trichur,
Kerala State, India.
The effect of certain food additives on
aflatoxin production by Aspergillus
parasiticus has been studied in vitro.
Extracts of turmeric (Curcuma longa), garlic
(Allium sativum) and asafoetida (Ferula
asafoetida) inhibited the aflatoxin
production considerably (more than 90%) at
concentrations of 5-10 mg/ml. Similar
results were also seen using butylated
hydroxytoluene, butylated hydroxyanisole and
ellagic acid at concentration 0.1 mM.
Curcumin, the antioxidant principle from
Curcuma longa did not have any effect on
aflatoxin production. Turmeric and curcumin
were also found to reverse the aflatoxin
induced liver damage produced by feeding
aflatoxin B1 (AFB1) (5 micrograms/day per 14
days) to ducklings. Fatty changes, necrosis
and biliary hyperplasia produced by AFB1
were considerably reversed by these food
additives.
PMID: 1394115 [PubMed - indexed for MEDLINE]
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Hydrolyzable tannins: potent inhibitors
of hydroperoxide production and tumor
promotion in mouse skin treated with
12-O-tetradecanoylphorbol-13-acetate in
vivo.
Gali HU,
Perchellet EM,
Klish DS,
Johnson JM,
Perchellet JP.
Anti-Cancer Drug Laboratory, Kansas State
University, Manhattan 66506.
The anti-oxidant and the
anti-tumor-promotion activities of several
hydrolyzable tannins (HTs), including a
commercial tannic-acid (TA) mixture, were
examined in mouse skin treated with
12-O-tetradecanoylphorbol-13-acetate (TPA)
in vivo. A single application of TPA
gradually increases the hydroperoxide (HPx)-producing
activity of the epidermis, which is
maximally stimulated at 3 days and returns
to control levels at 9 days. Pre-treatments
with TA and ellagic acid (EA) strongly
inhibit, in a dose-dependent manner, this
HPx response to TPA. Total inhibition by TA
lasts for about 16 hr, beyond which it is
substantially reduced but not completely
lost. TA can also reduce the level of
epidermal HPx when it is applied 36 hr after
the tumor promoter. EA is an antioxidant 10
times more potent than TA and n-propyl
gallate (PG), which are equally effective
against TPA-induced HPx production. Gallic
acid is the least effective of the HTs in
inhibiting HPx formation. TA also inhibits
the production of HPx induced by several
structurally different tumor promoters and
the greater HPx responses produced by
repeated TPA treatments. When applied 20 min
before each promotion treatment, twice a
week for 45 weeks, several HTs inhibit the
incidence and yield of papillomas and
carcinomas promoted by TPA in initiated
skin. Overall, TA is more effective than EA
and PG in inhibiting skin-tumor promotion by
TPA, suggesting that the anti-oxidant
effects of HTs are essential but not
sufficient for their anti-tumor-promotion
activity.
Publication Types:
PMID: 1592533 [PubMed - indexed for MEDLINE]
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Antitumor-promoting activities of
hydrolyzable tannins in mouse skin.
Gali HU,
Perchellet EM,
Klish DS,
Johnson JM,
Perchellet JP.
Division of Biology, Kansas State
University, Manhattan 66506-4901.
Ellagic acid and gallic acid and its
derivatives, applied topically to female
CF-1 mice 20 min before each
12-O-tetradecanoylphorbol-13-acetate (TPA)
treatment inhibit the inductions of
epidermal ornithine decarboxylase activity,
hydroperoxide production and DNA synthesis
caused by this potent tumor promoter in
relation with their abilities to inhibit the
promotion of skin papillomas and carcinomas
in the two-step initiation-promotion
protocol. Because of its potency against TPA
promotion, tannic acid, which is already
known to inhibit tumor initiation, may
inhibit the multistage process of
carcinogenesis.
Publication Types:
PMID: 1576722 [PubMed - indexed for MEDLINE]
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The effect of ellagic acid on xenobiotic
metabolism by cytochrome P-450IIE1 and
nitrosodimethylamine mutagenicity.
Wilson T,
Lewis MJ,
Cha KL,
Gold B.
Eppley Institute for Research in Cancer and
Allied Diseases, University of Nebraska
Medical Center, Omaha 68198-6805.
Ellagic acid (EA) is an inhibitor of the in
vitro mutagenicity of N-nitrosodimethylamine
(NDMA) in Salmonella typhimurium strain
TA100 using pyrazole-induced rat liver 9000
x g supernatant (S-9). In order to
understand this activity, the effect of EA
on the metabolic hydroxylation of
4-nitrophenol, a substrate, as is NDMA, for
cytochrome P-450IIE1 was studied using
pyrazole induced rat S-9 and microsomal
protein. It is shown that EA has an
inhibitory effect on 4-nitrophenol
hydroxylase with both enzyme preparations.
This effect on cytochrome P-450IIE1 may be
responsible, at least in part, for the
inhibition of NDMA mutagenicity by EA.
Publication Types:
PMID: 1730135 [PubMed - indexed for MEDLINE]
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Biodistribution of ellagic acid and
dose-related inhibition of lung
tumorigenesis in A/J mice.
Boukharta M,
Jalbert G,
Castonguay A.
Laboratory of Cancer Etiology and
Chemoprevention, School of Pharmacy, Laval
University, Quebec City, Canada.
Ellagic acid (EA), derived from fruit
ellagitannins, is known to be antimutagenic
and anticarcinogenic in various animal tumor
models. In this study, EA at a dose of 4
g/kg diet inhibited multiplicity of tumors
induced by
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) in A/J mice by 54%. This inhibition
was dose related between 0.06 and 4.0 g/kg
diet. In contrast, two related compounds,
esculin and esculetin, had no effect on lung
tumorigenesis. The biodistribution of EA was
studied as a function of dose and time after
gavage of EA. The levels of EA in the lung
were directly proportional to the dose of EA
between 0.2 and 2.0 mmol. The maximum level
of EA, corresponding to 21.3 nmol/g, was
observed 30 minutes after gavage with 2.0
mmol of EA/kg body wt, which corresponds to
only 70 ppm of the administered dose. The
levels in liver tissues were 10-fold lower
and reached a maximum 30 minutes after
gavage. At this interval, the blood level of
EA was 1 nmol/ml. The inclusion of EA in
cyclodextrin doubles the level of EA in lung
tissues. These results demonstrate that EA
localizes preferentially in lung tissues and
confirm that EA administered orally can
inhibit lung tumorigenesis.
Publication Types:
PMID: 1437655 [PubMed - indexed for MEDLINE]
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Antitumor-promoting activities of tannic
acid, ellagic acid, and several gallic acid
derivatives in mouse skin.
Perchellet JP,
Gali HU,
Perchellet EM,
Klish DS,
Armbrust AD.
Anti-Cancer Drug Laboratory, Kansas State
University, Manhattan 66506-4901.
Naturally occurring plant phenols with
antimutagenic and anticarcinogenic
activities were tested for their abilities
to inhibit the biochemical and biological
effects of the potent tumor promoter
12-O-tetradecanoyl-phorbol-13-acetate (TPA)
in mouse epidermis in vivo. When applied
topically to mouse skin, tannic acid (TA),
ellagic acid, and several gallic acid
derivatives all inhibit TPA-induced
ornithine decarboxylase activity,
hydroperoxide production, and DNA synthesis,
three biochemical markers of skin tumor
promotion. Moreover, in the two-step
initiation-promotion protocol, the same
phenolic compounds also inhibit the
incidence and yield of skin tumors promoted
by TPA. TA is the most effective of these
treatments. Since they are already known to
inhibit tumor initiation, the plant phenols
protecting against skin tumor promotion by
TPA may be universal inhibitors of
multistage carcinogenesis. TA and other
polyphenols, therefore, might be valuable in
cancer therapy and/or prevention.
Publication Types:
PMID: 1417700 [PubMed - indexed for MEDLINE]
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Prevention by chemopreventive agents of
azoxymethane-induced foci of aberrant crypts
in rat colon.
Pereira MA,
Khoury MD.
Environmental Health Research and Testing,
Inc., Cincinnati, OH 45245.
Foci of aberrant crypts are putative
preneoplastic lesions of colon cancer that
can be detected in unsectioned colons
stained with methylene blue. The ability of
this assay to demonstrate chemopreventive
activity was evaluated. Male Sprague-Dawley
rats received two subcutaneous injections 1
week apart, of 15 mg/kg azoxymethane each.
The animals started to receive the test
agents in their diet 1 week prior to the
first injection of azoxymethane and
continuously until killed 5 weeks later. The
number of foci of aberrant crypts induced by
the treatment of azoxymethane was reduced
from 228 foci/animal without any
chemopreventive agent to 151 foci/animal by
N-acetylcysteine; to 121 foci/animal by
dehydroepiandrosterone; to 161 by alpha-difluoromethylornithine;
and to 121 by
1,2-oxothiazolidine-4-carboxylate. The other
agents (diallyl sulfide, ellagic acid and
phenethyl isothiocyanate) did not
significantly alter the number of
foci/animal induced by azoxymethane. Animals
that did not receive azoxymethane had an
average of 0.72 foci/animal. Our results
suggest that four of the tested agents might
reduce azoxymethane-induced colon cancer,
which requires confirmation. Further
validation of the foci of aberrant crypt in
the colon assay to screen chemicals for
chemoprevention agents is warranted.
PMID: 1837244 [PubMed - indexed for MEDLINE]
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