Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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81:
Cancer Lett. 1999 Mar
1;136(2):215-21.
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p53/p21(WAF1/CIP1) expression and its
possible role in G1 arrest and apoptosis in
ellagic acid treated cancer cells.
Narayanan BA,
Geoffroy O,
Willingham MC,
Re GG,
Nixon DW.
Cancer Prevention Program, Hollings Cancer
Center, Medical University of South Carolina,
Charleston 29425, USA. bhagavati@musc.edu
Ellagic acid is a phenolic compound present in
fruits and nuts including raspberries,
strawberries and walnuts. It is known to
inhibit certain carcinogen-induced cancers and
may have other chemopreventive properties. The
effects of ellagic acid on cell cycle events
and apoptosis were studied in cervical
carcinoma (CaSki) cells. We found that ellagic
acid at a concentration of 10(-5) M induced G
arrest within 48 h, inhibited overall cell
growth and induced apoptosis in CaSki cells
after 72 h of treatment. Activation of the cdk
inhibitory protein p21 by ellagic acid
suggests a role for ellagic acid in cell cycle
regulation of cancer cells.
PMID: 10355751 [PubMed - indexed for MEDLINE]
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Protective effect of curcumin, ellagic acid
and bixin on radiation induced genotoxicity.
Thresiamma KC,
George J,
Kuttan R.
Amala Cancer Research Centre, Amala Nagar,
Trichur, Kerala State, India.
Induction of micronuclei and chromosomal
aberrations produced by whole body exposure of
r-radiation (1.5-3.0 Gy) in mice was found to
be significantly inhibited by oral
administration of natural antioxidants,
curcumin (400 micro moles), ellagic acid (200
micro moles) and bixin (200 micro moles) per
kilogram body weight. These antioxidants
induced inhibition of micronucleated
polychromatic and normochromatic erythrocytes,
was comparable with alpha-tocopherol (200
micro moles) administration. Curcumin and
ellagic acid were also found to significantly
reduce the number of bone marrow cells with
chromosomal aberrations and chromosomal
fragments as effectively as alpha-tocopherol.
Moreover, administration of antioxidants
inhibited the DNA strand breaks produced in
rat lymphocytes upon radiation as seen from
the DNA unwinding studies. These results
indicated that antioxidant curcumin, ellagic
acid and bixin provide protection against
chromosome damage produced by radiation.
Publication Types:
PMID: 10089063 [PubMed - indexed for MEDLINE]
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Determining efficacy of cancer
chemopreventive agents using a cell-free
system concomitant with DNA adduction.
Smith WA,
Gupta RC.
Graduate Center for Toxicology, Room 354,
Health Sciences Research Building, University
of Kentucky Medical Center, Lexington, KY
40536-0305, USA.
The large (>2000) and expanding number of
natural and synthetic agents with potential
cancer chemopreventive properties renders it
economically and physically impossible to test
each of these agents for their efficacy in the
widely accepted 2-year animal bioassay and
clinical trials. Therefore, there is a growing
need for relevant short-term screening tests
to study these compounds such that only the
most efficacious ones undergo extensive
long-term studies. We have previously reported
in a pilot study that the use of a microsome-mediated
test system concomitant with DNA adduction is
a pertinent and relevant model for rapidly
studying the efficacy and mechanisms of cancer
chemopreventive agents. We have extended this
study to investigate 26 additional agents for
their potential chemopreventive abilities by
studying their effects on microsome-mediated
benzo[a]pyrene (BP)-DNA adduction. These
agents had differential effects on the two
major adducts of BP-DNA, i.e.,
BP-7,8-diol-9,10-epoxide (BPDE)-deoxyguanosine
(dG) and 9-OH-BP-dG-derived adducts. These
agents were therefore categorized into five
classes. Three test agents (ellagic acid,
genistein and oltipraz) were strong inhibitors
of both adducts. These agents diminished
BP-DNA adduction by 65-95% and were
categorized as Class I agents. Six other
agents (benzyl isocyanate, R(+)-1-phenylethyl
isocyanate, linoleic acid ethyl ester,
(+)-biotin, indole-3-carboxylic acid and
beta-carotene) moderately inhibited both
BP-DNA adducts (25-64%); these compounds were
identified as Class II agents. Six additional
test agents inhibited only one adduct
selectively and nine others were ineffective;
these agents were categorized as Class III and
Class IV, respectively. Interestingly, seven
test agents enhanced BPDE-dG or 9-OH-BP-dG or
both adducts and were categorized as Class V
agents. Four of these Class V agents
concomitantly inhibited BPDE-dG while
enhancing 9-OH-BP-dG. This emphasizes the
importance of studying individual DNA adducts
in contrast to total DNA binding. In
conclusion, Class I and Class II agents may be
good candidates for further chemoprevention
studies. Copyright 1999 Elsevier Science B.V.
Publication Types:
PMID: 10082925 [PubMed - indexed for MEDLINE]
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Polyphenols inhibit promotional phase of
tumorigenesis: relevance of superoxide
radicals.
Kaul A,
Khanduja KL.
Department of Biophysics, Postgraduate
Institute of Medical Education and Research,
Chandigarh, India.
Ellagic acid (EA), tannic acid (TA), caffeic
acid (CA), and ferulic acid (FA) offer
considerable promise as anticarcinogens. The
role of these dietary polyphenols was
investigated in the promotional phase of
carcinogenesis. Topical application of
polyphenols simultaneously with
phorbol-12-myristate-13-acetate (PMA) or
mezerein resulted in significant protection
against
7,12-dimethyl-benz[a]anthracene-induced skin
tumors in mice. Caffeic acid was the most
effective inhibitor of tumor promotion. In
vivo and in vitro treatment of murine
peritoneal macrophages with the tumor
promoters resulted in stimulation of
superoxide anion radical formation. Tannic
acid, caffeic acid, and ferulic acid were
stronger inhibitors of PMA- and mezerein-induced
superoxide anion radical than ellagic acid in
in vivo and in vitro conditions. Treatment of
[1(3)-14C]glycerol- or [methyl-14C]choline
chloride-labeled resident or thioglycollate-elicited
macrophages with PMA and mezerein led to
accumulation of radioactive diacylglycerol
equivalents. The polyphenols were capable of
inhibiting these releases.
Publication Types:
PMID: 9919616 [PubMed - indexed for MEDLINE]
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Effects of dietary anticarcinogens on rat
gastrointestinal glutathione S-transferase
theta 1-1 levels.
van Lieshout EM,
Bedaf MM,
Pieter M,
Ekkel C,
Nijhoff WA,
Peters WH.
Department of Gastroenterology, St Radboud
University Hospital, Nijmegen, The
Netherlands.
Several naturally occurring food components or
non-steroidal anti-inflammatory drugs (NSAIDs)
may reduce gastrointestinal cancer rates.
Recently we have shown that dietary
administration of such compounds enhanced the
glutathione S-transferase (GST) enzyme
activity and class alpha, mu and pi isoenzyme
levels in the rat gastrointestinal tract.
Elevation of the levels of GSTs, a family of
biotransformation enzymes with many functions
such as detoxification of carcinogens, might
be one of the mechanisms that lead to cancer
prevention. We therefore investigated whether
the anticarcinogens alpha-angelicalactone,
alpha-tocopherol, beta-carotene, coumarin,
ellagic acid, flavone, indole-3-carbinol,
d-limonene, oltipraz, phenethylisothiocyanate
(PEITC) and the sulphoraphane analogue
compound-30 affect gastrointestinal rGSTT1-1
protein levels in male Wistar rats. rGSTT1-1
protein levels were determined in cytosolic
fractions of liver and oesophageal-, gastric-,
small intestinal- and colonic mucosa by
densitometrical analyses of western blots
after immunodetection with an anti human
GSTT1-1 monoclonal antibody, that cross-reacts
with rGSTT1-1. In control Wistar rats,
gastrointestinal rGSTT1-1 protein levels were
highest in the liver and decreased in the
order liver > stomach > colon > oesophagus >
small intestine. Gastric rGSTT1-1 protein
levels were enhanced by alpha-angelicalactone,
alpha-tocopherol, coumarin, ellagic acid,
oltipraz, PEITC and the sulphoraphane analogue
compound-30. Oesophageal rGSTT1-1 protein
levels were elevated by a-angelicalactone and
coumarin, whereas colonic rGSTT1-1 protein
levels were elevated by coumarin. Ellagic
acid, on the other hand, reduced hepatic
rGSTT1-1 protein levels to 53% of the control.
In conclusion, dietary anticarcinogens are
capable of inducing rGSTT1-1 protein levels in
the rat gastrointestinal tract, and are most
pronounced in the stomach. Enhanced rGSTT1-1
protein levels might lead to an increase of
enzyme activity and to a more efficient
detoxification of carcinogens and thus could
contribute to prevention of carcinogenesis.
Publication Types:
PMID: 9855024 [PubMed - indexed for MEDLINE]
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Biodistribution of, antimutagenic
efficacies in Salmonella typhimurium of, and
inhibition of P450 activities by ellagic acid
and one analogue.
Castonguay A,
Boukharta M,
Teel R.
Laboratory of Cancer Etiology and
Chemoprevention, Faculty of Pharmacy, Laval
University, Quebec City, Canada G1K 7P4.
Ellagic acid (EA) is generated by hydrolysis
of ellagitannins present in fruit berries and
edible nuts and grapes. Large doses of EA
prevent lung tumorigenesis induced by the
tobacco carcinogen
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) in A/J mice. In this study, we document
the efficacies of the EA structural analogue
(3,4,7,8-tetrahydroxy-6H-benzo[b,d]pyran-6-one)
(analogue 1) to inhibit specific P450
activities, pulmonary metabolism of NNK in A/J
mice, and NNK-induced mutations in Salmonella
typhimurium. Mouse lung microsomes metabolized
benzyloxyresorufin, a marker of cytochrome
P450 2B1 activity, more extensively than
methoxyresorufin or ethoxyresorufin. The EA
analogue was more effective than EA in
inhibiting dealkylation of the three
alkoxyresorufins, suggesting that it is a
nonspecific inhibitor of P450s. Mouse lung
microsomes hydroxylate testosterone in the
7alpha and 6beta positions, suggesting
contributions of P450 2A1 and P450 3A2
isozymes, respectively. Inhibition of both
pathways was more effective with the EA
analogue than with EA. Mouse lung explants
metabolized NNK by alpha-carbon hydroxylation
(activation) and pyridine N-oxidation
(deactivation). Both pathways were inhibited
when 100 microM EA was added to the culture
medium. The EA analogue was a better inhibitor
of the activation of NNK to electrophilic
species than EA. Mouse lung microsomes
activate NNK to intermediates mutagenic to S.
typhimurium. Inhibition of NNK mutagenicity by
EA or the EA analogue was 20 or 65%,
respectively. The distribution of the EA
analogue in lung and liver was determined
following gavage with 1.7 mmol of the EA
analogue. In the lung, a maximal level of EA
analogue corresponding to 105 nmol was
observed 30 min after administration of the
analogue. The level in liver tissues was
4-fold lower than in the lung. Results of this
study demonstrate that the EA analogue is more
effective than EA in inhibiting the pulmonary
activation of NNK and suggest that the EA
analogue could be effective in preventing lung
tumorigenesis.
Publication Types:
PMID: 9815185 [PubMed - indexed for MEDLINE]
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[Phenolic acid intake of adults in a
Bavarian subgroup of the national food
consumption survey]
[Article in German]
Radtke J,
Linseisen J,
Wolfram G.
Institut für Ernährungswissenschaft der TU
München, Freising-Weihenstephan.
Phenolic acids, essentially hydroxycinnamic
acids and hydroxybenzoic acids, are secondary
plant products and commonly found in plant
derived foodstuff. The antioxidant and
anticarcinogenic properties of phenolic acids
could be one of the facts to explain the
inverse association between fruit and
vegetable intake and the incidence of coronary
heart disease and cancer, respectively, as
found in epidemiologic studies. Phenolic acids
are rarely listed in food composition tables
and there are no dietary intake data
available. Consequently, a data base
containing the phenolic acid content of foods
(literatur data) was built and 7-d dietary
protocols of 63 women and 56 men of a Bavarian
subpopulation (age 19-49 years) of the German
National Food Consumption Survey (NVS) were
evaluated. The average phenolic acid intake of
men and women is 222 mg/d within a large
range. The dominating one within all the
phenolic acids is clearly caffeic acid (206
mg/d); the intake of the other phenolic acids
amounts to 0.2 (gentisic acid) up to 5.2 mg/d
(ellagic acid). The sum of hydroxybenzoic
acids and hydroxycinnamic acids amounts to 11
mg/d and 211 mg/d, respectively. Significant
sex differences are found for some of the
phenolic acids. Especially, the average intake
of caffeic acid of women (229 mg/d) is higher
than that of men (179 mg/d) caused by the high
amount of coffee consumption. The age group
"25-49 years" is consuming more coffee than
the age group "19-24 years" and, therefore,
reveals a significantly higher intake of
caffeic acid. The major sources of phenolic
acids are coffee with 92% of the caffeic acid
intake and fruits (including fruit products
and juices) with 75% of the salycilic acid and
59% of the p-coumaric acid intake.
Consequently, phenolic acids are consumed in
considerable amounts with food. Since
antioxidant and anticarcinogenic properties of
phenolic acids are already proven in in vitro
as well as in animal experiments,
epidemiologic studies will show whether a high
phenolic acid intake goes ahead with a reduced
risk for coronary heart disease or cancer in
humans.
Publication Types:
PMID: 9698647 [PubMed - indexed for MEDLINE]
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Effect of cancer chemopreventive agents on
microsome-mediated DNA adduction of the breast
carcinogen dibenzo[a,l]pyrene.
Smith WA,
Arif JM,
Gupta RC.
Graduate Center for Toxicology, University of
Kentucky Medical Center, Lexington 40536-0305,
USA.
Due to the large and expanding number of
potential cancer chemopreventive agents, there
is an increasing need for short term tests to
study the efficacy and mechanisms of these
agents. In this study, we have employed a
microsome-mediated test system to study the
effect of several suspected chemopreventive
agents on the DNA adduct formation capacity of
the potent mammary carcinogen,
dibenzo[a,l]pyrene (DBP). Bioactivation of DBP
by Aroclor 1254-induced rat liver microsomes
in the presence of calf thymus DNA (300 microg/ml)
resulted in the formation of one major and six
other prominent DNA adducts (324 adducts/10(7)
nucleotides). These adducts were previously
determined to be deoxyadenosine (dA) and
deoxyanosine (dG)-derivatives of both anti-
and syn-DBP-11,12-diol-13,14-epoxides (DBPDE).
Intervention with ellagic acid, chlorophyllin,
benzyl isocyanate (BIC), oltipraz or genistein
(150 microM) strongly diminished DBP-DNA
adduction by > or = 75%. Linoleic acid,
curcumin and butylated hydroxytoluene (BHT)
also significantly inhibited DBP DNA adduction
(26-46%) while N-acetylcysteine (NAC) had no
effect. Moreover, nonenzymatic studies with
anti- and syn-DBPDE isomers revealed that
chlorophyllin, ellagic acid, BIC and BHT may
be inhibiting DBP-DNA adduction in an
enzymatic-independent manner since these
agents diminished DBPDE-DNA adduction by
30-75%. Genistein, oltipraz and curcumin did
not diminish DBPDE-DNA adduction and therefore
most likely require the presence of the
microsomal subcellular fraction to inhibit DBP-DNA
adduction.
Publication Types:
PMID: 9600699 [PubMed - indexed for MEDLINE]
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Mechanism of action of fotemustine, a new
chloroethylnitrosourea anticancer agent:
evidence for the formation of two DNA-reactive
intermediates contributing to cytotoxicity.
Hayes MT,
Bartley J,
Parsons PG,
Eaglesham GK,
Prakash AS.
National Research Centre for Environmental
Toxicology, Queensland, Australia.
Methyl excision repair deficient human tumor
cells (Mer-) were found to be hypersusceptible
to killing by the antimelanoma agent
fotemustine (FM) implicating alkylation of O6
guanine as the major contributor to toxicity.
Preincubation of the drug in aqueous solution
for 5 min resulted in an immediate reduction
in cytotoxicity (35-50%), in vitro DNA
alkylation (31%), and DNA interstrand
cross-linking (40%) followed by a second
reaction with considerably slower kinetics.
Electrospray ionisation mass spectrometry (ESI-MS)
showed that in aqueous solution FM rearranged
rapidly to form either a metastable tautomer
or decomposed to form a highly reactive
diazohydroxide (t1/2 < 2 min). These results
suggest the presence of two DNA-reactive
species relevant to biological activity.
Coincubation of ellagic acid (an inhibitor of
O6-guanine alkylation) with FM inhibited in
vitro ISC, suggesting that the O6-chloroethyl
lesion is the predominant cause of the
cross-link. On the basis of these findings, we
propose that FM breaks down to form a
short-lived intermediate,
2-chloroethyldiazohydroxide, which rapidly
generates O6-guanine lesions responsible for
the drug's initial activity and a long lived
iminol tautomer responsible for the remaining
O6 guanine alkylation and cytotoxicity.
Publication Types:
PMID: 9271495 [PubMed - indexed for MEDLINE]
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Protective effect of food additives on
aflatoxin-induced mutagenicity and
hepatocarcinogenicity.
Soni KB,
Lahiri M,
Chackradeo P,
Bhide SV,
Kuttan R.
Amala Cancer Research Centre, Kerala State,
India.
Food additives such as turmeric (Curcuma longa),
and active ingredient curcumin (diferuloyl
methane), asafoetida (flavouring agent),
butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT) and ellagic acid were
found to inhibit the mutagenesis induced by
aflatoxin B1 (AFB1) (0.5 microg/plate) in
Salmonella tester strains TA 98 and TA 100.
Turmeric and curcumin, which were the most
active, inhibited mutation frequency by more
than 80% at concentrations of 2 microg/plate.
Other food additives were also significantly
effective. Dietary administration of turmeric
(0.05%), garlic (0.25%), curcumin and ellagic
acid (0.005% each) to rats significantly
reduced the number of gammaglutamyl
transpeptidase-positive foci induced by AFB1
which is considered as the precursor of
hepatocellular neoplasm. These results
indicate the usefulness of antioxidant food
additives in ameliorating aflatoxin-induced
mutagenicity and carcinogenicity.
Publication Types:
PMID: 9149115 [PubMed - indexed for MEDLINE]
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Isothiocyanates and plant polyphenols as
inhibitors of lung and esophageal cancer.
Stoner GD,
Morse MA.
Division of Environmental Health Sciences, The
Ohio State University School of Public Health,
Columbus 43210, USA.
A group of arylalkyl isothiocyanates were
tested for their abilities to inhibit
tumorigenicity and DNA methylation induced by
both the tobacco-specific nitrosamine, NNK, in
A/J mouse lung and the esophageal-specific
carcinogen, NMBA, in F344 rat esophagus. In
addition, ellagic acid was tested for its
ability to inhibit NMBA-induced esophageal
tumorigenesis. In the strain A lung tumor
model, PEITC effectively inhibited NNK-induced
lung tumors at a dose of 5 micromol, but was
not inhibitory at lower doses. PPITC, PBITC,
PPeITC, and PHITC were all considerably more
potent inhibitors of NNK lung tumorigenesis
than PEITC, and PHITC was the most potent
inhibitor of all. Thus, in the strain A lung
tumor model, there was a trend of increased
inhibitory efficacy among arylalkyl
isothiocyanates with increased alkyl chain
length. In the F344 rat esophageal tumor
model, PPITC was clearly more potent than
PEITC, BITC and PBITC had little inhibitory
effect on esophageal tumorigenesis, and in a
separate experiment, PHITC actually enhanced
esophageal tumorigenesis. Thus, the
structure-activity relationships for
inhibition of tumorigenesis by arylalkyl
isothiocyanates were considerably different in
the two animal models. However, the effects of
the isothiocyanates on tumorigenesis were
well-correlated to their effects on DNA adduct
formation in either model. The most likely
mechanism of inhibition of tumorigenesis by
these isothiocyanates is via inhibition of the
cytochrome p450 enzymes responsible for
activation of NNK in mouse lung or NMBA in rat
esophagus. Ellagic acid was an effective
inhibitor of esophageal tumorigenesis,
although not as potent as PEITC or PPITC. Like
the isothiocyanates, ellagic acid inhibits
cytochrome p450-mediated activation of NMBA.
PMID: 9103268 [PubMed - indexed for MEDLINE]
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Experimental evidence for cancer preventive
elements in foods.
Wargovich MJ.
Department of Gastrointestinal Medical
Oncology and Digestive Diseases, The
University of Texas M.D. Anderson Cancer
Center, Houston, USA.
The last decade has witnessed an incredible
advance in our understanding of how fruits and
vegetables work to prevent cancer.
Epidemiological studies have suggested that a
diet rich in fruits and vegetables is
associated with reduced risk for a number of
common cancers. Food chemists and natural
product scientists have identified hundreds of
'phytochemicals' that are being evaluated for
the prevention of cancer. Food components can
modify carcinogenesis in one of five different
ways. They may: (1) modify carcinogen
activation by inhibiting Phase 1 enzymes; (2)
modify how carcinogens are detoxified through
Phase 2 pathways; (3) scavenge DNA reactive
agents; (4) suppress the abnormal
proliferation of early, preneoplastic lesions;
and (5) inhibit certain properties of the
cancer cell.
Publication Types:
PMID: 9103245 [PubMed - indexed for MEDLINE]
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Chemoprevention of colorectal cancer.
Krishnan K,
Brenner DE.
Department of Internal Medicine, James H.
Quillen College of Medicine, East Tennessee
State University, Johnson City, USA.
This review summarizes the principles of
cancer chemoprevention and discusses the
evidence from epidemiologic and experimental
studies and preclinical and clinical trials of
potential colorectal chemopreventive agents.
The putative mechanisms of action of the drugs
in chemoprevention and their potential to
reduce the incidence and mortality rate of
colorectal neoplasms are discussed. The future
of colorectal chemoprevention will depend on
important new insights into molecular
carcinogenesis of colorectal cancer,
application of molecular markers as surrogate
endpoints, and ultimately on therapeutic
targets of prevention in clinical trials.
Publication Types:
PMID: 8960895 [PubMed - indexed for MEDLINE]
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Organ specific, protocol dependent
modulation of 7,12-dimethylbenz[a]anthracene
carcinogenesis in rainbow trout (Oncorhynchus
mykiss) by dietary ellagic acid.
Harttig U,
Hendricks JD,
Stoner GD,
Bailey GS.
Department of Food Science and Technology,
Oregon State University, Corvallis 97331-6602,
USA.
This study investigated pre-initiation and
post-initiation effects of dietary ellagic
acid (EA) on 7,12-dimethylbenz[a]anthracene (DMBA)
multi-organ carcinogenesis in rainbow trout (Oncorhynchus
mykiss). EA at 100, 250 (study 2), 1000 and
2000 (study 1) p.p.m. suppressed stomach
adenopapilloma incidence by 33, 60, 70 and 78%
(P < or = 0.001), respectively, as well as
tumor multiplicity (P < 0.01) and size (P <
0.001) when fed continuously following DMBA
initiation. However, continuous EA feeding
also produced modest (250 p.p.m.) to extensive
(1000, 2000 p.p.m.) growth rate suppression in
these studies. Retrospective logistic
regression modeling of the data allowed
separation of growth-related from
non-growth-related inhibitory effects. By this
approach: (i) tumor development showed a
similarly strong dependence (same regression
slope) on animal growth rate in all treatment
groups; (ii) EA-mediated reduction in mean
population growth contributed to suppressed
stomach tumor response above 250 p.p.m. EA;
and (iii) even at high, toxic doses EA
displayed inhibitory mechanisms additional to,
and distinct from, growth suppression effect.
The effects of post-initiation EA were organ
specific. Chronic EA treatment significantly
suppressed swim-bladder as well as stomach
tumor incidence at doses > or = 1000 p.p.m.,
but increased liver tumor incidence at doses >
or = 250 p.p.m. Three protocols examined EA
effects on the initiation process. EA fed at
1000 p.p.m. concurrently with 750 p.p.m.
dietary DMBA for 7 weeks modestly reduced
stomach tumor incidence (from 85 to 78%, P <
0.05) and multiplicity (from 6.3 +/- 4.3 to
4.9 +/- 2.9, P < 0.01), but did not alter
swim-bladder or liver response. The effect of
EA pretreatment prior to DMBA single-dose
initiation by gill uptake was also examined.
When fed for 1 week prior to initiation, 2000
p.p.m. EA again imposed a small reduction in
stomach adenoma incidence (from 88 to 78%; P <
0.05) and multiplicity (from 5.5 +/- 3.2 to
4.4 +/- 3.2; P < 0.01). However, when EA was
pre-fed for 3 weeks instead of 1 week,
protection in the stomach was lost and
response in liver and swim-bladder
significantly increased. In sum, these studies
demonstrate that EA influence on DMBA
tumorigenesis in this multi-organ model is
highly protocol dependent and organ specific.
Post-initiation dietary EA consistently
suppressed stomach tumor development in trout,
at EA doses far lower than those required for
protection in rodents. At higher doses,
however, EA also displayed toxicity and a
potential in some protocols to enhance tumor
response in other organs.
Publication Types:
PMID: 8968055 [PubMed - indexed for MEDLINE]
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Inhibition of liver fibrosis by ellagic
acid.
Thresiamma KC,
Kuttan R.
Amala Cancer Research Centre, Amala Nagar,
Trichur, Kerala.
Chronic administration of carbon tetrachloride
in liquid paraffin (1.7) ip; 0.15 ml, (20
doses) has been found to produce severe
hepatotoxicity, as seen from the elevated
levels of serum and liver glutamate-pyruvate
transaminase, alkaline phosphatase and lipid
peroxides. The chronic administration of
carbon tetrachloride was also found to produce
liver fibrosis as seen from pathological
analysis as well as elevated liver-hydroxy
proline. Oral administration of ellagic acid
was found to significantly reduce the elevated
levels of enzymes, lipid peroxide and liver
hydroxy proline in these animals and rectified
liver pathology. These results indicate that
ellagic acid administration orally can
circumvent the carbon tetrachloride toxicity
and subsequent fibrosis.
PMID: 9055108 [PubMed - indexed for MEDLINE]
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Protective effect of curcumin, ellagic acid
and bixin on radiation induced toxicity.
Thresiamma KC,
George J,
Kuttan R.
Amala Cancer Research Centre, Amala Nagar,
Thrissur, India.
Whole body irradiation of rats (10 Gy as five
fractions) found to produce lung fibrosis
within 2 months as seen from increased lung
collagen hydroxyproline and histopathology.
Oral administration of antioxidants curcumin,
ellagic acid, bixin and alpha-tocopherol at a
concentration 200 mumole/kg body weight
significantly reduced the lung collagen
hydroxyproline in these animals. In serum and
liver lipid peroxidation which were found to
be increased by irradiation was reduced
significantly by antioxidant treatment. The
liver superoxide dismutase and glutathione
peroxidase activity were also found to be
increased and catalase activity decreased in
irradiated control. Superoxide dismutase
activity reduced significantly by antioxidant
treatment while catalase activity was found to
be increased with alpha-tocopherol treatment.
The increased frequency of micronucleated
polychromatic erythrocytes after whole body
irradiation of mice was found to be
significantly reduced with antioxidants.
Publication Types:
PMID: 9014516 [PubMed - indexed for MEDLINE]
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Use of a microsome-mediated test system to
assess efficacy and mechanisms of cancer
chemopreventive agents.
Smith WA,
Gupta RC.
Graduate Center for Toxicology and Preventive
Medicine, University of Kentucky Medical
Center, Lexington, KY 40536-0305, USA.
There is a growing need for short-term assays
which can assess the mechanisms and efficacy
of cancer chemopreventive agents. In the
present study we have employed a microsome-mediated
test system concomitantly with DNA adduct
detection to assess the efficacy of five
chemopreventive agents, N-acetylcysteine,
butylated hydroxytoluene (BHT), curcumin,
oltipraz, and ellagic acid. 32P-Postlabeling
analysis of DNA incubated with benzo[a]pyrene
(BP) in the presence of Aroclor 1254-induced
microsomes produced two major adducts: one
derived from the interaction of
benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)
with deoxyguanosine (dG) and the other from
further activation of 9-OH-BP (309 and 34
adducts/10(7) nucleotides, respectively). With
the exception of N-acetylcysteine, all test
agents significantly altered BP-DNA adduct
levels: Intervention with ellagic acid and
oltipraz substantially (64-94%) inhibited both
BPDE-dG and 9-OH-BP adducts, while
intervention with curcumin and BHT inhibited
the BPDE-dG adduct (57% and 38%, respectively)
and enhanced the 9-OH-BP adduct (230% and
650%, respectively). Furthermore, ellagic acid
was the only test agent observed to inhibit
the anti BPDE-dG adduct in the absence of
microsomal enzymes, which is consistent with
the known conjugation of ellagic acid with
BPDE. These results suggest that oltipraz may
be acting as an inhibitor of P4501A1, the
isozyme involved in activation of BP to BPDE,
or by conjugation of the electrophilic species
by a metabolite of oltipraz. A plausible
mechanism for inhibition of the BPDE-dG adduct
and enhancement of the 9-OH-BP adduct by
curcumin and BHT includes inhibition of
epoxide hydrolase. Our results also indicate
that N-acetylcysteine does not act as an
electrophilic trapping agent of BP metabolites
but may exert its protective effect in vivo by
various other means, including modulation of
detoxification enzymes and altering DNA repair
processes. These data suggest that this
cell-free system in conjunction with the
sensitive 32P-postlabeling DNA adduct analysis
may prove a viable test system for assessing
the mechanisms and efficacy of chemopreventive
agents.
Publication Types:
PMID: 8681444 [PubMed - indexed for MEDLINE]
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Flavonoids, potent inhibitors of the human
P-form phenolsulfotransferase. Potential role
in drug metabolism and chemoprevention.
Eaton EA,
Walle UK,
Lewis AJ,
Hudson T,
Wilson AA,
Walle T.
Department of Cell and Molecular Pharmacology
and Experimental Therapeutics, Medical
University of South Carolina, Charleston
29425,USA.
The common dietary constituent quercetin was a
potent inhibitor of sulfoconjugation of
acetaminophen and minoxidil by human liver
cytosol, partially purified P-form
phenolsulfotransferase (PST), and recombinant
P-form PST, with IC50 values of 0.025-0.095
microM. Quercetin inhibition of acetaminophen
was noncompetitive with respect to acceptor
substrate, with a Ki value of 0.067 microM. A
number of other flavonoids, such as fisetin,
galangin, myricetin, kaempferol, chrysin, and
apigenin, were also potent inhibitors of
P-form PST-mediated sulfation, with IC50
values < 1 microM. Studies of structural
analogs indicated the flavonoid 7-hydroxyl
group as particularly important for potent
inhibition. Potential human metabolites of
quercetin were poor inhibitors. Curcumin,
genistein, and ellagic acid (other
polyphenolic natural products) were also
inhibitors of P-form PST, with IC50 values of
0.38-34.8 microM. Quercetin was also shown to
inhibit sulfoconjugation by the human hepatoma
cell line Hep G2. Although less potent in this
intact cell system (IC50 2-5 microM),
quercetin was still more potent than
2,6-dichloro-4-nitrophenol, the classical
P-form PST inhibitor that has been shown to be
an inhibitor also in vivo. These observations
suggest the potential for clinically important
drug interactions, as well as a possible role
for flavonoids as chemopreventive agents in
sulfation-induced carcinogenesis.
PMID: 8742236 [PubMed - indexed for MEDLINE]
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-
Regional chemoprevention of
carcinogen-induced tumors in rat colon.
Liu T,
Mokuolu AO,
Rao CV,
Reddy BS,
Holt PR.
Gastrointestinal Division, St.
Luke's-Roosevelt Hospital Center, College of
Physicians and Surgeons, Columbia University,
New York, USA.
BACKGROUND & AIMS: Rat colon neoplasms are
distributed 60% in the distal colon (DC) and
40% in the proximal colon (PC), similar to
distribution of colon cancers in the
industrialized world. The effects of
chemopreventive agents that affect colon tumor
incidence on the distribution of colon tumors
were studied. METHODS: Colon tumor
distribution, numbers, and volumes were
measured in the DC and PC of rats administered
azoxymethane (15 mg/kg subcutaneously 2x) as
an initiating agent and fed diets containing
various chemopreventive agents. RESULTS: In
control rats, azoxymethane-induced tumor
incidence in the DC exceeded that in the PC,
but tumor volume was greater in the PC than
the DC. Ellagic acid showed no chemopreventive
effect and maintained the PC-DC colon tumor
gradient. Oltipraz, a modestly effective
chemopreventive agent, principally reduced the
incidence of DC tumors. DL-d-difluoromethylornithine
also greatly altered tumor number in the DC
compared with the PC. In contrast, piroxicam
(400 ppm) reduced PC tumors by 82% but DC
tumors only by 57%. With all regimens, tumor
volume remained greater in the PC than the DC.
CONCLUSIONS: Chemopreventive agents have a
selective regional effect on colon
tumorigenesis in the rat. Elucidation of the
mechanism for these differences may help
clarify the modes of action of chemopreventive
agents in colon cancer.
Publication Types:
PMID: 7557082 [PubMed - indexed for MEDLINE]
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-
Chemoprevention of diethylnitrosamine-induced
liver foci and hepatocellular adenomas in C3H
mice.
Pereira MA.
Environmental Health Research and Testing,
Inc., Lexington, Kentucky 40503, USA.
The ability of six proposed chemopreventive
agents to prevent diethylnitrosamine-induced
liver foci and tumors in male C3H mice was
investigated. The test agents were
administered by intraperitoneal injection on
days 13, 14 and 15 of age and starting at 21
days of age continuously in the diet until
sacrifice at 161 days of age. The mice were
administered 4.0 mg/kg diethylnitrosamine by
intraperitoneal injection on day 15 of age and
two hours after the test agent.
Diethylnitrosamine-induced 62.4 +/- 4.2 foci
of altered hepatocytes and 22.1 +/- 2.1
hepatocellular adenomas, which were reduced by
diallyl sulfide to 21.6 +/- 2.4 and 6.73 +/-
1.13 and phenethyl isothiocyanate to 28.2 +/-
3.4 and 5.06 +/- 1.53 foci and adenomas,
respectively. Difluoromethylornithine and
ellagic acid only decreased the yield of
adenomas without affecting the yield of foci
of altered hepatocytes and of total lesions.
N-Acetyl-l-cysteine and
1,2-oxothiazolidine-4-carboxylate did not
affect the yield of either liver lesion. When
administered starting prior to
diethylnitrosamine-initiation and continuing
until sacrifice, diallyl sulfide and phenethyl
isothiocyanate demonstrated chemoprevention of
tumorigenesis.
Publication Types:
PMID: 8572583 [PubMed - indexed for MEDLINE]
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