Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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61:
Mutat Res. 2003
Feb-Mar;523-524:163-72.
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Mechanism-based in vitro screening of
potential cancer chemopreventive agents.
Gerhäuser C,
Klimo K,
Heiss E,
Neumann I,
Gamal-Eldeen A,
Knauft J,
Liu GY,
Sitthimonchai S,
Frank N.
Division of Toxicology and Cancer Risk Factors,
C010-2 Chemoprevention, German Cancer Research
Center, Im Neuenheimer Feld 280, 69120
Heidelberg, Germany. c.gerhauser@dkfz.de
Identification and use of effective cancer
chemopreventive agents have become an important
issue in public health-related research. For
identification of potential cancer
chemopreventive constituents we have set up a
battery of cell- and enzyme-based in vitro
marker systems relevant for prevention of
carcinogenesis in vivo. These systems include
modulation of drug metabolism (inhibition of
Cyp1A activity, induction of NAD(P)H:quinone
reductase (QR) activity in Hepa1c1c7 murine
hepatoma cell culture), determination of radical
scavenging (DPPH scavenging) and antioxidant
effects (scavenging of superoxide anion-,
hydroxyl- and peroxyl-radicals),
anti-inflammatory mechanisms (inhibition of
lipopolysaccharide (LPS)-mediated nitric oxide
(NO) generation by inducible NO synthase (iNOS)
in Raw 264.7 murine macrophages,
cyclooxygenase-1 (Cox-1) inhibition), and
anti-tumor promoting activities (inhibition of
phorbol ester-induced ornithine decarboxylase (ODC)
activity in 308 murine keratinocytes). We have
tested a series of known chemopreventive
substances belonging to several structural
classes as reference compounds for the
identification of novel chemopreventive agents
or mechanisms. These include organosulfur
compounds (phenethylisothiocyanate (PEITC),
diallylsulfide, diallyldisulfide), terpenes
(limonene, perillyl alcohol, oleanolic acid,
18-beta-glycyrrhetinic acid), short-chain fatty
acids (sodium butyrate), indoles
(indole-3-carbinol), isoflavonoids (quercetin,
silymarin, genistein), catechins ((-)-epigallocatechin
gallate (EGCG)), simple phenols (ellagic acid,
resveratrol, piceatannol, curcumin),
pharmaceutical agents (piroxicam,
acetylsalicylic acid, tamoxifen), and
vitamins/derivatives (ascorbic acid, Trolox). We
confirmed known chemopreventive mechanisms of
these compounds. Additionally, we could
demonstrate the usefulness of our approach by
identification of hitherto unknown mechanisms of
selected agents. As an example, we detected
anti-inflammatory properties of PEITC, based on
NF-kappaB-mediated inhibition of NO production.
Further, PEITC inhibited phorbol ester-induced
superoxide anion radical production in
granulocytes, and ODC induction in the 308 cell
line. These mechanisms might contribute to the
chemopreventive potential of PEITC. Copyright
2002 Elsevier Science B.V.
Publication Types:
PMID: 12628514 [PubMed - indexed for MEDLINE]
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Antioxidant regulation of protein kinase C in
cancer prevention.
Gopalakrishna R,
Gundimeda U.
Department of Cell and Neurobiology, Keck School
of Medicine, University of Southern California,
Los Angeles 90089, USA. rgopalak@usc.edu
Besides scavenging free radicals, antioxidants
inhibit signaling enzymes such as protein kinase
C (PKC) that play a crucial role in tumor
promotion. By having different oxidation
susceptible regions, PKC can respond to both
oxidant tumor promoters and cancer-preventive
antioxidants to elicit opposite cellular
responses. Oxidant tumor promoters activate PKC
by reacting with zinc-thiolates present within
the regulatory domain. In contrast, the oxidized
forms of some cancer-preventive agents, such as
polyphenolics (ellagic acid, 4-hydroxytamoxifen
and curcumin) and selenocompounds, can
inactivate PKC by oxidizing the vicinal thiols
present within the catalytic domain. This brings
an efficient counteractive mechanism to block
the signal transduction induced by tumor
promoters at the first step itself. Because
prostate cancer prevention clinical trials in
large human population are under way, we have
focused more on understanding the
cancer-preventive mechanism of selenium.
Methylselenol, the postulated cancer-preventive
metabolite, has no direct effect on PKC
activity. However, methylseleninic acid, locally
generated by the reaction of membrane
methylselenol with PKC-bound tumor-promoting
fatty acid hydroperoxides, selectively
inactivates PKC. This mechanism clarifies how
the volatile methylselenol that is present in a
low concentration induces the inactivation of
PKC selectively in the promoting precancer
cells. Selenoprotein thioredoxin reductase
reverses selenium-induced inactivation of PKC,
suggesting that selenoproteins may serve as a
safeguard against the toxicity induced by
selenometabolites. Moreover, this also explains
how a resistance to selenium develops in
advanced malignant cells. The redox-mediated
inactivation of PKC may, at least in part, be
responsible for the antioxidant-induced
inhibition of tumor promotion and cell growth,
as well as for the induction of cell death.
Publication Types:
PMID: 12468631 [PubMed - indexed for MEDLINE]
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Inhibition of cancer cell growth by crude
extract and the phenolics of Terminalia chebula
retz. fruit.
Saleem A,
Husheem M,
Härkönen P,
Pihlaja K.
Department of Chemistry, University of Turku,
Kiinamyllynkatu 10, FIN-20014 Turku, Finland.
amsale@utu.fi
A 70% methanol extract of Terminalia chebula
fruit, was studied for its effects on growth in
several malignant cell lines including a human
(MCF-7) and mouse (S115) breast cancer cell
line, a human osteosarcoma cell line (HOS-1), a
human prostate cancer cell line (PC-3) and a
non-tumorigenic, immortalized human prostate
cell line (PNT1A) using assays for proliferation
([(3)H]-thymidine incorporation and coulter
counting), cell viability (ATP determination)
and cell death (flow cytometry and Hoechst DNA
staining). In all cell lines studied, the
extract decreased cell viability, inhibited cell
proliferation, and induced cell death in a dose
dependent manner. Flow cytometry and other
analyses showed that some apoptosis was induced
by the extract at lower concentrations, but at
higher concentrations, necrosis was the major
mechanism of cell death. ATP assay guided
chromatographic fractionation of the extract
yielded ellagic acid,
2,4-chebulyl-beta-D-glucopyranose (a new natural
product), and chebulinic acid which were tested
by ATP assay on HOS-1 cell line in comparison to
three known antigrowth phenolics of Terminalia,
gallic acid, ethyl gallate, luteolin, and tannic
acid. Chebulinic acid (IC(50) = 53.2 microM +/-
0.16) > tannic acid (IC(50) = 59.0 microg/ml +/-
0.19) > and ellagic acid (IC(50) = 78.5 microM
+/- 0.24), were the most growth inhibitory
phenolics of T. chebula fruit in our study.
Publication Types:
PMID: 12127233 [PubMed - indexed for MEDLINE]
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Interactive gene expression pattern in
prostate cancer cells exposed to phenolic
antioxidants.
Narayanan BA,
Narayanan NK,
Stoner GD,
Bullock BP.
Microarray Systems Laboratory, American Health
Foundation, Valhalla, NY 10595, USA. bhagavat@mindspring.com
Dietary phenolic compounds are known to elicite
vital cellular responses such as cell cycle
arrest, apoptosis and differentiation by
activating a cascade of molecular events. As
there is an increasing interest to improve the
efficacy of these compounds for use as potential
chemopreventive agents, we wanted to understand
the impact of phenolic compounds on target genes
in prostate cancer. In this study we used human
cDNA microarrays with 2400 clones consisting of
17 prosite motifs to characterize alterations in
gene expression pattern in response to the
phenolic antioxidants ellagic acid (EA) and
resveratrol (RE). Over a 48-hr exposure of
androgen - sensitive LNCaP cells to EA and RE, a
total of 593 and 555 genes respectively, showed
more than a two fold difference in expression. A
distinct set of genes in both EA-and RE-treated
cells may represent the signature profile of
phenolic antioxidant-induced gene expression in
LNCaP cells. Although extensive similarity was
found between effects of EA - and RE -
responsive genes in prostate cancer cells, out
of 246 genes with overlapping responses, 25
genes showed an opposite effect. Quantitative
RT-PCR was used to verify and validate the
differential expression of selected genes
identified from cDNA microarrays. In-depth
analysis of the data from this study provided
insight into the alterations in the p53 -
responsive genes, p300, Apaf-1, NF-kBp50 and p65
and PPAR families of genes, suggesting the
activation of multiple signaling pathways that
leads to growth inhibition of LNCaP cells. This
is a first study to look for changes in a large
number of human genes in response to dietary
compounds.
Publication Types:
PMID: 12002526 [PubMed - indexed for MEDLINE]
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Effects of lyophilized black raspberries on
azoxymethane-induced colon cancer and
8-hydroxy-2'-deoxyguanosine levels in the
Fischer 344 rat.
Harris GK,
Gupta A,
Nines RG,
Kresty LA,
Habib SG,
Frankel WL,
LaPerle K,
Gallaher DD,
Schwartz SJ,
Stoner GD.
Department of Food Sciences and Technology,
College of Food, Agriculture, and Environmental
Sciences, Ohio State University, Columbus, OH
43210, USA.
This study examined the effects of lyophilized
black raspberries (BRB) on azoxymethane (AOM)-induced
aberrant crypt foci (ACF), colon tumors, and
urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG)
levels in male Fischer 344 rats. AOM was
injected (15 mg/kg body wt i.p.) once per week
for 2 wk. At 24 h after the final injection, AOM-treated
rats began consuming diets containing 0%, 2.5%,
5%, or 10% (wt/wt) BRB. Vehicle controls
received 5% BRB or diet only. Rats were
sacrificed after 9 and 33 wk of BRB feeding for
ACF enumeration and tumor analysis. ACF
multiplicity decreased 36%, 24%, and 21% (P <
0.01 for all groups) in the 2.5%, 5%, and 10%
BRB groups, respectively, relative to the AOM-only
group. Total tumor multiplicity declined 42%,
45%, and 71% (P < 0.05 for all groups). Although
not significant, a decrease in tumor burden
(28%, 42%, and 75%) was observed in all BRB
groups. Adenocarcinoma multiplicity decreased
28%, 35%, and 80% (P < 0.01) in the same
treatment groups. Urinary 8-OHdG levels were
reduced by 73%, 81%, and 83% (P < 0.01 for all
groups). These results indicate that BRB inhibit
several measures of AOM-induced colon
carcinogenesis and modulate an important marker
of oxidative stress in the Fischer 344 rat.
Publication Types:
PMID: 11962247 [PubMed - indexed for MEDLINE]
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Chemoprevention of heterocyclic amine-induced
mammary carcinogenesis in rats.
Hirose M,
Nishikawa A,
Shibutani M,
Imai T,
Shirai T.
Division of Pathology, National Institute of
Health Sciences, Tokyo, Japan. m-hirose@nihs.go.jp
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
(PhIP) is one of the most prevalent carcinogenic
heterocyclic amines in the environment,
targeting the colon, prostate, pancreas, and
mammary gland in rodents. Chemopreventive
effects of synthetic and naturally occurring
compounds on PhIP-induced rat mammary
carcinogenesis were investigated in a series of
experiments. In a PhIP feeding model, groups of
20-21 female F344 rats each, were treated with
0.02% PhIP alone or PhIP plus 0.5%
1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), 1%
green tea catechins, 1% alpha-tocopherol, 0.1%
ellagic acid, or 1% chlorophyllin, each in the
diet, or 0.1% caffeine in drinking water for 52
weeks. To assess the mechanism of HTHQ and
caffeine inhibition of PhIP-induced
carcinogenesis, effects of these compound on the
in vitro metabolic activation of PhIP were
examined in the presence of S9 mix. In the next
series of experiments, the PhIP intragastric
dose model was applied to allow separate
investigation of the effects of chemicals during
the initiation and postinitiation periods. In
these experiments, female Sprague-Dawley rats
were given eight intragastric doses of 100 mg/kg
body weight during the first 4-8 weeks for
initiation. Either during initiation or after
initiation, or only after initiation, animals
were treated with either corn or perilla oil at
doses of 5 and 20%, conjugated fatty acid
derived from safflower oil (CFA-S) or perilla
oil (CFA-P) at a dose of 1%, arctiin at doses of
0.02 and 0.2% in the diet, or sodium nitrite
(NaNO(2)) at a dose of 0.2% in drinking water.
In the PhIP feeding model, administration of
PhIP alone for 52 weeks induced adenocarcinomas
in 40% of rats, but the incidence was remarkably
reduced to 5% by the simultaneous treatment with
0.5% HTHQ, a strong lipophilic phenolic
antioxidant, or to 10% by 0.1% caffeine.
Administration of 1% chlorophyllin exerted
similar, albeit weaker, effects. alpha-Tocopherol
at a dose of 0.5% only reduced the multiplicity
of carcinomas, and 1% green tea catechins only
the mean size of mammary tumors. In a metabolic
activation study of PhIP, HTHQ and caffeine
clearly inhibited the formation of metabolites.
In the PhIP gastric dose model, among the
naturally occurring compounds examined, a plant
lignan arctiin, perilla oil, which contains a
large amount of n-6 alpha-linolenic acid, and
CFA-S or CFA-P inhibited mammary tumor
development, particularly in the postinitiation
period, although a clear dose response was not
observed. Treatment with 0.2% NaNO(2) in the
initiation period was found to lower the volume
of mammary tumors. The present results indicate
that a number of compounds may be candidate
chemopreventive agents against PhIP-induced
mammary carcinogenesis, acting through different
mechanisms and depending on the stage of
carcinogenesis. Copyright 2002 Wiley-Liss, Inc.
Publication Types:
PMID: 11921198 [PubMed - indexed for MEDLINE]
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Strong antioxidant activity of ellagic acid
in mammalian cells in vitro revealed by the
comet assay.
Festa F,
Aglitti T,
Duranti G,
Ricordy R,
Perticone P,
Cozzi R.
Dipartimento di Biologia, Università degli Studi
Roma TRE, Italy.
Oxidative stress due to oxygen and various
radical species is associated with the induction
of DNA single- and double-strand breaks and is
considered to be a first step in several human
degenerative diseases, cancer and ageing.
Naturally occurring antioxidants are being
extensively analysed for their ability to
protect DNA against such injury. We studied
three naturally occuring compounds, Ascorbic
Acid, Melatonin and Ellagic acid, for their
ability to modulate DNA damage produced by two
strong radical oxygen inducers (H2O2 and
Bleomycin) in cultured CHO cells. The alkaline
Comet assay was used to measure DNA damage and a
cytofluorimetric analysis was performed to
reveal the intracellular oxidative species. The
data showed a marked reduction of H2O2- and
Bleomycin-induced DNA damage exerted by Ellagic
Acid. On the contrary Ascorbic acid and
Melatonin appeared to induce a slight increase
in DNA damage per se. In combined treatments,
they caused a slight reduction of H2O2-induced
damage, but they did not efficiently modulate
the Bleomycin-induced one. The
Dichlorofluorescein diacetate (DCFH-DA)
cytofluorimetric test confirmed the strong
scavenging action exerted by Ellagic Acid.
Publication Types:
PMID: 11911267 [PubMed - indexed for MEDLINE]
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Ellagic [correction of ellagica] acid
inhibits arylamine N-acetyltransferase activity
and DNA adduct formation in human bladder tumor
cell lines (T24 and TSGH 8301).
Lin SS,
Hung CF,
Tyan YS,
Yang CC,
Hsia TC,
Yang MD,
Chung JG.
Department of Radiological Technology, Chungtai
Institute of Health Sciences and Technology,
Taichung, Taiwan, Republic of China.
The fact that vitamin C (ascorbic acid) exhibits
a protective effect in certain types of cancer
is well documented. Our previous studies
demonstrated that human bladder tumor cell line
(T24) has N-acetyltransferase (NAT) activity in
cytosols and intact cells. The present studies
examined the inhibition of arylamine NAT
activity and carcinogen (2-aminofluorene)-DNA
adduct formation by ellagic acid (EA) in human
bladder tumor cell lines (T24 and TSGH 8301).
Two assay systems were performed, one with
cellular cytosols (9,000 g supernatant), the
other with intact bladder tumor cell
suspensions. NAT activity and
2-aminofluorene-DNA adduct formation in T24 and
TSGH 8301 cells was inhibited by EA in a
dose-dependent manner in both systems, i.e.. the
greater the concentration of EA in the reaction
the greater the inhibition of NAT activity
(dose- and time-course dependent effects). The
data also indicated that EA decreased the
apparent Km and Vmax of NAT enzymes from T24 and
TSGH 8301 cells in cytosols. NAT activity and
2-aminofluorene-DNA adducts in T24 is higher
than in TSGH 8301. This report is the first to
demonstrate that EA affects human bladder tumor
cell NAT activity.
Publication Types:
PMID: 11828989 [PubMed - indexed for MEDLINE]
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Ellagic acid inhibits nucleoside diphosphate
kinase-B activity.
Malmquist NA,
Anzinger JJ,
Hirzel D,
Buxton IL.
Department of Pharmacology, University of Nevada
School of Medicine, Reno, Nevada 89557, USA.
Publication Types:
PMID: 11793995 [PubMed - indexed for MEDLINE]
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Antiproliferative constituents in the plant
8. Seeds of Rhynchosia volubilis.
Kinjo J,
Nagao S,
Tanaka T,
Nonaka GI,
Okabe H.
Faculty of Pharmaceutical Sciences, Fukuoka
University, Japan. kinjojun@fukuoka-u.ac.jp
The MeOH extract of the seeds of Rhynchosia
volubilis (Leguminosae) showed antiproliferative
activity against human gastric adenocarcinoma
[MK-1, 50% growth inhibition (GI50): 25 microg/ml],
human uterus carcinoma (HeLa, GI50: 30 microg/ml),
and murine melanoma (B16F10, GI50: 8 microg/ml)
cells. Bioactivity-guided fractionation resulted
in the isolation of gallic acid methylester (1),
gallic acid (2), 7-O-galloylcatechin (3),
1,6-di-O-galloylglucose (4), 1-O-galloylglucose
(5), and trigalloylgallic acid (6), and their
antiproliferative activity was estimated. All
showed much stronger inhibition against B16F10
cell growth than against HeLa and MK-1 cell
growth. Compound 2 and its tetramer (6) with a
free carboxyl group showed higher activity than
those which did not have a free carboxyl group.
In relation to the gallic acid tetramer (6), two
gallic acid dimers (ellagic acid and
dehydrodigallic acid) and trimers (tergallic
acid dilactone and flavogallonic acid dilactone)
were tested for their activity, and compared
with those of the isolates.
Publication Types:
PMID: 11767121 [PubMed - indexed for MEDLINE]
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Chemoprevention of esophageal tumorigenesis
by dietary administration of lyophilized black
raspberries.
Kresty LA,
Morse MA,
Morgan C,
Carlton PS,
Lu J,
Gupta A,
Blackwood M,
Stoner GD.
Division of Environmental Health Sciences,
School of Public Health, Comprehensive Cancer
Center, The Ohio State University, Columbus,
Ohio 43210, USA.
Fruit and vegetable consumption has consistently
been associated with decreased risk of a number
of aerodigestive tract cancers, including
esophageal cancer. We have taken a "food-based"
chemopreventive approach to evaluate the
inhibitory potential of lyophilized black
raspberries (LBRs) against N-nitrosomethylbenzylamine
(NMBA)-induced esophageal tumorigenesis in the
F344 rat, during initiation and postinitiation
phases of carcinogenesis. Anti-initiation
studies included a 30-week tumorigenicity
bioassay, quantification of DNA adducts, and
NMBA metabolism study. Feeding 5 and 10% LBRs,
for 2 weeks prior to NMBA treatment (0.25 mg/kg,
weekly for 15 weeks) and throughout a 30-week
bioassay, significantly reduced tumor
multiplicity (39 and 49%, respectively). In a
short-term bioassay, 5 and 10% LBRs inhibited
formation of the promutagenic adduct
O(6)-methylguanine (O(6)-meGua) by 73 and 80%,
respectively, after a single dose of NMBA at
0.25 mg/kg. Feeding 5% LBRs also significantly
inhibited adduct formation (64%) after NMBA
administration at 0.50 mg/kg. The postinitiation
inhibitory potential of berries was evaluated in
a second bioassay with sacrifices at 15, 25, and
35 weeks. Administration of LBRs began after
NMBA treatment (0.25 mg/kg, three times per week
for 5 weeks). LBRs inhibited tumor progression
as evidenced by significant reductions in the
formation of preneoplastic esophageal lesions,
decreased tumor incidence and multiplicity, and
reduced cellular proliferation. At 25 weeks,
both 5 and 10% LBRs significantly reduced tumor
incidence (54 and 46%, respectively), tumor
multiplicity (62 and 43%, respectively),
proliferation rates, and preneoplastic lesion
development. Yet, at 35 weeks, only 5% LBRs
significantly reduced tumor incidence and
multiplicity, proliferation indices and
preneoplastic lesion formation. In conclusion,
dietary administration of LBRs inhibited events
associated with both the initiation and
promotion/progression stages of carcinogenesis,
which is promising considering the limited
number of chemopreventives with this potential.
Publication Types:
PMID: 11507061 [PubMed - indexed for MEDLINE]
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Effect of chemopreventive agents on DNA
adduction induced by the potent mammary
carcinogen dibenzo[a,l]pyrene in the human
breast cells MCF-7.
Smith WA,
Freeman JW,
Gupta RC.
Graduate Center for Toxicology, 354 Health
Sciences Research Building, University of
Kentucky Medical Center, Lexington, KY
40536-0305, USA.
Over 1500 structurally diverse chemicals have
been identified which have potential cancer
chemopreventive properties. The efficacy and
mechanisms of this growing list of
chemoprotective agents may be studied using
short-term bioassays that employ relevant
end-points of the carcinogenic process. In this
study, we have examined the effects of eight
potential chemopreventive agents, N-acetylcysteine
(NAC), benzylisocyanate (BIC), chlorophyllin,
curcumin, 1,2-dithiole-3-thione (D3T), ellagic
acid, genistein, and oltipraz, on DNA adduction
of the potent mammary carcinogen
dibenzo[a,l]pyrene (DBP) using the human breast
cell line MCF-7. Bioactivation of DBP by MCF-7
cells resulted in the formation of one
predominant (55%) dA-derived and several other
dA- or dG-derived DNA adducts. Three test
agents, oltipraz, D3T, and chlorophyllin
substantially (>65%) inhibited DBP-DNA adduction
at the highest dose tested (30 microM). These
agents also significantly inhibited DBP adduct
levels at a lower dose of 15 microM, while
oltipraz was effective even at the lowest dose
of 5 microM. Two other agents, genistein and
ellagic acid were moderate (45%) DBP-DNA adduct
inhibitors at the highest dose tested, while NAC,
curcumin, and BIC were ineffective. These
studies indicate that the MCF-7 cell line is an
applicable model to study the efficacy of cancer
chemopreventive agents in a human setting.
Moreover, this model may also provide
information regarding the effect of the test
agents on carcinogen bioactivation and
detoxification enzymes.
Publication Types:
PMID: 11506803 [PubMed - indexed for MEDLINE]
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Quinone isomers of the WS-5995 antibiotics:
synthetic antitumor agents that inhibit
macromolecule synthesis, block nucleoside
transport, induce DNA fragmentation, and
decrease the growth and viability of L1210
leukemic cells more effectively than ellagic
acid and genistein in vitro.
Perchellet EM,
Sperfslage BJ,
Qabaja G,
Jones GB,
Perchellet JP.
Anti-Cancer Drug Laboratory, Kansas State
University, Division of Biology, Ackert Hall,
Manhattan, KS 66506-4901, USA.
Antibiotic WS-5995A (code name J4) and two of
its synthetic analogs, o-quinone J1 and model p-quinone
J7, which show some structural similarity with
both ellagic acid (EA) and genistein (GEN), were
compared for their antileukemic activity in
L1210 cells in vitro. Overall, J4 is more
cytostatic and cytotoxic than J1 and J7,
suggesting that methyl and methoxy
substitutions, a p-quinone moiety, and a
hydrogen bonding phenolic group may enhance the
antitumor potential of these naphthoquinone
lactones, which are all more potent than EA and
GEN. For instance, the lead compound J4 inhibits
tumor cell proliferation and viability at day 4
(IC(50): 0.24--0.65 microM) more effectively
than EA (IC(50): 5--6 microM) and GEN (IC(50): 7
microM). Since J4 does not increase but rather
decreases the mitotic index of L1210 cells at 24
h, it is not an antitubulin drug but might
arrest early stages of cell cycle progression
like EA and GEN. A 1.5- to 3-h pretreatment with
J4 is sufficient to inhibit the rates of DNA,
RNA and protein syntheses (IC(50): 2.0--2.5
microM) determined over 30- to 60-min periods of
pulse-labeling in L1210 cells in vitro, whereas
EA (IC(50): 20-130 microM) and GEN (IC(50):
40--115 microM) are less effective against
macromolecule synthesis. In contrast to 156
microM EA, which is inactive, a 15-min
pretreatment with 10--25 microM J4 has the
advantage of also inhibiting the cellular
transport of both purine and pyrimidine
nucleosides over a 30 s period in vitro, an
effect which can be mimicked by 156 microM GEN.
Hence, the WS-5995 analogs and GEN may prevent
the incorporation of [(3)H]adenosine and
[(3)H]thymidine into DNA because they rapidly
block the uptake of these nucleosides by the
tumor cells. After 24 h, the
concentration-dependent induction of DNA
cleavage by J4 peaks at 10 microM and declines
at 25 microM, whereas EA and GEN are ineffective
at 10 microM but maximally stimulate DNA
cleavage at 62.5 microM. Like EA and GEN, the
mechanism by which J4 induces DNA fragmentation
is inhibited by actinomycin D, cycloheximide,
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl
ketone, N-tosyl-L-phenylalanine chloromethyl
ketone and ZnSO(4), suggesting that J4 triggers
apoptosis by caspase and endonuclease
activation. Because they are more potent than EA
and GEN, and affect both nucleoside transport
and DNA cleavage, the WS-5995 antitumor
antibiotics might be valuable in
polychemotherapy to potentiate the action of
antimetabolites and sensitize multidrug-resistant
tumor cells.
Publication Types:
PMID: 11395569 [PubMed - indexed for MEDLINE]
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IGF-II down regulation associated cell cycle
arrest in colon cancer cells exposed to phenolic
antioxidant ellagic acid.
Narayanan BA,
Re GG.
American Health Foundation, 1, Dana Road
Valhalla, NY 10595, USA. bhagavat@earthlink.net
Altered cell and tissue differentiation is
characteristic of premalignant lesions long
before they become invasive and metastatic. One
approach to controlling preneoplastic lesions is
to block their expansion with non-toxic agents
that suppress cell proliferation and induce
apoptosis. Here, we show that ellagic acid, a
natural, dietary phenolic antioxidant when given
at 10(-5) M for 48 hours to colon cancer cells
(SW 480), induced down regulation of insulin
like growth factor IGF-II, activated
p21(waf1/Cip1), mediated a cumulative effect on
G1/S transition phase and caused apoptotic cell
death. SW480 colon cancer cells expressed
significant mRNA levels for the mitogenic
insulin like growth factor (IGF-II).
Collectively, these observations suggest that
growth inhibition by ellagic acid is mediated by
signaling pathways that mediate DNA damage,
triggers p53, which in turn activates p21 and at
the same time alters the growth factor
expression, resulting in the down regulation of
IGF-II.
Publication Types:
PMID: 11299762 [PubMed - indexed for MEDLINE]
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Erratum in:
Inhibition of cellular transformation by
berry extracts.
Xue H,
Aziz RM,
Sun N,
Cassady JM,
Kamendulis LM,
Xu Y,
Stoner GD,
Klaunig JE.
Division of Toxicology, Department of
Pharmacology and Toxicology, Indiana University
School of Medicine, Indianapolis, IN, USA.
Recent studies have examined and demonstrated
the potential cancer chemopreventive activity of
freeze-dried berries including strawberries and
black raspberries. Although ellagic acid, an
abundant component in these berries, has been
shown to inhibit carcinogenesis both in vivo and
in vitro, several studies have reported that
other compounds in the berries may also
contribute to the observed inhibitory effect. In
the present study, freeze-dried strawberries (Fragara
ananassa, FA) or black raspberries (Rubus
ursinus, RU) were extracted, partitioned and
chromatographed into several fractions (FA-F001,
FA-F003, FA-F004, FA-F005, FA-DM, FA-ME from
strawberries and RU-F001, RU-F003, RU-F004,
RU-F005, RU-DM, RU-ME from black raspberries).
These extracts, along with ellagic acid, were
analyzed for anti-transformation activity in the
Syrian hamster embryo (SHE) cell transformation
model. None of the extracts nor ellagic acid by
themselves produced an increase in morphological
transformation. For assessment of
chemopreventive activity, SHE cells were treated
with each agent and benzo[a]pyrene (B[a]P) for 7
days. Ellagic acid, FA-ME and RU-ME fractions
produced a dose-dependent decrease in
transformation compared with B[a]P treatment
only, while other fractions failed to induce a
significant decrease. Ellagic acid, FA-ME and
RU-ME were further examined using a 24 h
co-treatment with B[a]P or a 6 day treatment
following 24 h with B[a]P. Ellagic acid showed
inhibitory ability in both protocols. FA-ME and
RU-ME significantly reduced B[a]P-induced
transformation only when co-treated with B[a]P
for 24 h. These results suggest that a methanol
extract from strawberries and black raspberries
may display chemopreventive activity. The
possible mechanism by which these methanol
fractions (FA-ME, RU-ME) inhibited cell
transformation appear to involve interference of
uptake, activation, detoxification of B[a]P
and/or intervention of DNA binding and DNA
repair.
PMID: 11181460 [PubMed - indexed for MEDLINE]
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Effects of ellagic acid by oral
administration on N-acetylation and metabolism
of 2-aminofluorene in rat brain tissues.
Lin SS,
Hung CF,
Ho CC,
Liu YH,
Ho HC,
Chung JG.
Department of Radiological Technology, Chungtai
Institute of Health Sciences and Technology,
Taichung, Taiwan, Republic of China.
Numerous studies have demonstrated that the
Acetyl Coenzyme A-dependent arylamine NAT enzyme
exist in many tissues of experimental animals
including humans, and that NAT has been shown to
be exist in mouse brain tissue. Increased NAT
activity levels are associated with increased
sensitivity to the mutagenic effects of
arylamine carcinogens. Attenuation of liver NAT
activity is related to breast and bladder cancer
processes. Therefore, the effects of ellagic
acid (EA) on the in vitro and in vivo N-acetylation
of 2-aminofluorene (AF) were investigated in
cerebrum, cerebellum and pineal gland tissues
from male Sprague-Dawley rats. For in vitro
examination, cytosols with or without EA
(0.5-500 microM) co-treatment decreased 7-72%,
15-63% and 10-78% of AF acetylation for
cerebrum, cerebellum and pineal gland tissues,
respectively. For in vivo examination, EA and AF
at the same time treated groups with all 3
examined tissues did show significant
differences (the changes of total amounts of AF
and AF metabolites based on the Anova analysis)
when compared to the ones without EA cotreatment
rats. The pretreatment of male rats with EA (10
mg/kg) 24 hr prior to the administration of AF
(50 mg/kg) (one day of EA administration suffice
to induce large changes in phase II enzyme
activity) resulted in a 76% decrease in total AF
and metabolites in pineal gland but did not show
significant differences in cerebrum and
cerebellum tissues. This is the first
demonstration to show that EA decreases the N-acetylation
of carcinogens in rat brain tissues.
PMID: 11071370 [PubMed - indexed for MEDLINE]
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Regulation of rat glutamate-cysteine ligase
(gamma-glutamylcysteine synthetase) subunits by
chemopreventive agents and in aflatoxin
B(1)-induced preneoplasia.
Shepherd AG,
Manson MM,
Ball HW,
McLellan LI.
Biomedical Research Centre, University of
Dundee, Ninewells Hospital and Medical School,
Dundee DD1 9SY, UK.
Certain dietary constituents can protect against
chemically induced carcinogenesis in rodents. A
principal mechanism by which these
chemopreventive compounds exert their protective
effects is likely to be via induction of
carcinogen detoxification. This can be mediated
by conjugation with glutathione, which is
synthesized by the sequential actions of
glutamate-cysteine ligase (GLCL) and glutathione
synthetase. We have demonstrated that dietary
administration of the naturally occurring
chemopreventive agents, ellagic acid, coumarin
or alpha-angelicalactone caused an increase in
GLCL activity of between approximately 3- and
5-fold in rat liver. Treatment with the
synthetic antioxidant ethoxyquin or the classic
inducer phenobarbital caused < 2-fold induction
of GLCL activity in rat liver, which was not
found to be significant. The increases in GLCL
activity were accompanied by increases (between
2- and 4-fold) in levels of both the catalytic
heavy subunit (GLCLC) and regulatory light
subunit (GLCLR). No substantial induction of
GLCL was observed in rat kidney. The glutathione
S-transferase (GST) subunits A1, A3, A4, A5, P1
and M1 were all found to be inducible in rat
liver by most of the agents. The greatest levels
of induction were observed for GST P1, following
treatment with coumarin (20-fold), alpha-angelicalactone
(10-fold) or ellagic acid (6-fold), and GST A5,
following treatment with coumarin (7-fold),
alpha-angelicalactone (6-fold) and ethoxyquin
(6-fold). Glutathione synthetase was induced
approximately 1.5-fold by coumarin, alpha-angelicalactone,
ellagic acid and ethoxyquin. The expression of
glutathione-related enzymes was also examined in
preneoplastic lesions induced in rat liver by
aflatoxin B(1). The majority of gamma-glutamyltranspeptidase
(GGT)-positive preneoplastic foci contained
increased levels of GLCLC relative to the
surrounding tissue. This was usually found to be
accompanied by an increase in GLCLR. Cells in
the inner cortex of rat kidney were found to
contain the highest levels of both GLCLC and
GLCLR. The same cells showed the strongest
staining for GGT activity.
Publication Types:
PMID: 11023540 [PubMed - indexed for MEDLINE]
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Isothiocyanates and freeze-dried strawberries
as inhibitors of esophageal cancer.
Stoner GD,
Kresty LA,
Carlton PS,
Siglin JC,
Morse MA.
Division of Environmental Health Sciences, The
Ohio State University School of Public Health,
and The Ohio State University Comprehensive
Cancer Center, The Ohio State University,
Columbus 43210, USA. stoner.21@osu.edu
A group of arylalkyl isothiocyanates were tested
for their abilities to inhibit tumorigenicity
and DNA methylation induced by the
esophageal-specific carcinogen, N-nitrosomethylbenzylamine
(NMBA) in the F344 rat esophagus. Phenylpropyl
isothiocyanate (PPITC) was more potent than
either phenylethyl isothiocyanate (PEITC) or
benzyl isothiocyanate (BITC). Phenylbutyl
isothiocyanate (PBITC), however, had a lesser
inhibitory effect on esophageal tumorigenesis,
and phenylhexyl isothiocyanate (PHITC) actually
enhanced esophageal tumorigenesis. Thus, the
two- and three-carbon isothiocyanates were more
effective inhibitors of NMBA-esophageal
carcinogenesis than the longer chain
isothiocyanates. The effects of the
isothiocyanates on tumorigenesis were well
correlated as to their effects on DNA adduct
formation. The most likely mechanism of
inhibition of tumorigenesis by these
isothiocyanates is via inhibition of the
cytochrome P450 enzymes responsible for the
metabolic activation of NMBA in rat esophagus. A
freeze-dried strawberry preparation was also
evaluated for its ability to inhibit NMBA-esophageal
tumorigenesis. It proved to be an effective
inhibitor, although not as potent as either
PEITC or PPITC. The inhibitory effect of the
berries could not be attributed solely to the
content of the chemopreventive agent, ellagic
acid, in the berries.
PMID: 10630596 [PubMed - indexed for MEDLINE]
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Tannins, xenobiotic metabolism and cancer
chemoprevention in experimental animals.
Nepka C,
Asprodini E,
Kouretas D.
Cytopathology Laboratory, Serres, Greece.
Tannins are plant polyphenolic compounds that
are contained in large quantities in food and
beverages (tea, red wine, nuts, etc.) consumed
by humans daily. It has been shown that various
tannins exert broad cancer chemoprotective
activity in a number of animal models. This
review summarizes the recent literature
regarding both the mechanisms involved, and the
specific organ cancer models used in laboratory
animals. An increasing body of evidence
demonstrates that tannins act as both
anti-initiating and antipromoting agents. In
view of the fact that tannins may be of valid
medicinal efficacy in human clinical trials, the
present review attempts to integrate results
from animal studies, and considers their
possible application in humans.
Publication Types:
PMID: 10510748 [PubMed - indexed for MEDLINE]
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Prevention of N-nitrosodiethylamine-induced
lung tumorigenesis by ellagic acid and quercetin
in mice.
Khanduja KL,
Gandhi RK,
Pathania V,
Syal N.
Department of Biophysics, Postgraduate Institute
of Medical Education & Research, Chandigarh,
India.
The polyphenolic antioxidants, consumed as an
integral part of vegetables, fruits and
beverages, are suggested as possessing
anticarcinogenic properties. In the present
study we have looked into the anticarcinogenic
potential of plant polyphenols ellagic acid (EA)
and quercetin against N-nitrosodiethylamine-induced
lung tumorigenesis in mice. Ellagic acid was
able to significantly reduce tumour incidence to
20% from the control value of 72.2%. Similarly,
tumour burden was also decreased, although not
significantly, from 3.15 to 2.5. Quercetin (QR)
caused the tumour incidence to decrease from
76.4% to 44.4% when fed until the third dose of
carcinogen. Both of the polyphenols suppressed
the tumour incidence mainly by acting at the
initiation phase of the carcinogenesis, since
continuing the feeding of polyphenols until the
termination of the experiment did not cause any
apparent change in tumour incidence or tumour
burden. Besides this, ellagic acid was found to
be a better chemopreventor than quercetin. In
order to search for their mechanism of action,
the effect of feeding of these compounds on
reduced glutathione (GSH), an important
endogenous antioxidant, and on lipid
peroxidation was investigated. Both ellagic acid
and QR caused a significant increase in GSH and
decrease in NADPH- and ascorbate-dependent lipid
peroxidation. Ellagic acid was found to be more
effective in decreasing the lipid peroxidation
and increasing the GSH. This may be one of the
reasons for its observed better anticarcinogenic
property as compared to quercetin.
PMID: 10418948 [PubMed - indexed for MEDLINE]
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