Nepka C, Asprodini E, Kouretas D
Eur J Drug Metab Pharmacokinet; 24(2):183-9 1999 UI: 99440448

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.

Lo HH, Hsieh SE, Tsai KJ, Chung JG
Drug Chem Toxicol; 22(3):555-62 1999 UI: 99374190

Arylamine N-acetyltransferase (NAT) activity in Pseudomonas aeruginosa was inhibited by ellagic acid (EA), a naturally occurring dietary plant phenol. By measuring the acetylation of 2-aminofluorene (2-AF), the NAT activity was determined. In P. aeruginosa ATCC 27853, a NAT activity of 1.37 +/- 0.25 nmol/min/10(10) CFU for intact cell and a NAT activity of 5.92 +/- 0.20 nmol/min/mg protein for cytosolic preparation were measured. EA (ranging from 1 to 0.125 mM) showed a dose-dependent inhibition of NAT activities in the analysis of both intact cell and cytosolic preparations. Enzymatic kinetics were determined and found that EA was a potent non-competitive inhibitor of NAT activity in P. aeruginosa ATCC 27853. EA inhibition of NAT activities in P. aeruginosa ATCC 27853 was time-dependent for at least 4 hrs. These data strongly indicated that EA could suppress NAT activity in P. aeruginosa.

Khanduja KL, Gandhi RK, Pathania V, Syal N
Food Chem Toxicol; 37(4):313-8 1999 UI: 99345316

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.

Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW
Cancer Lett; 136(2):215-21 1999 UI: 99281882

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.

Smith WA, Gupta RC
Mutat Res; 425(1):143-52 1999 UI: 99185178

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.

Stoner GD, Kresty LA, Carlton PS, Siglin JC, Morse MA
Toxicol Sci; 52(2 Suppl):95-100 1999 UI: 20094292

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.

Thresiamma KC, George J, Kuttan R
J Exp Clin Cancer Res; 17(4):431-4 1998 UI: 99186924

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.

Kaul A, Khanduja KL
Nutr Cancer; 32(2):81-5 1998 UI: 99118269

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.

van Lieshout EM, Bedaf MM, Pieter M, Ekkel C, Nijhoff WA, Peters WH
Carcinogenesis; 19(11):2055-7 1998 UI: 99070666

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.

Castonguay A, Boukharta M, Teel R
Chem Res Toxicol; 11(11):1258-64 1998 UI: 99034533

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.

Soliman KF, Mazzio EA
Proc Soc Exp Biol Med; 218(4):390-7 1998 UI: 98377887

Excessive nitric oxide (NO) production in the brain has been correlated with neurotoxicity and the pathogenesis of several neurodegenerative diseases. NO production from neuroglial cells surrounding neurons contributes significantly to the pathogenesis of these diseases. The suppression of NO production in these cells may be beneficial in retarding many of these disorders. The present study was designed to evaluate the capacity of dietary-derived polyphenolic compounds, flavonoids, crude extracts, oils, and other food constituents in suppressing the release of NO from lipopolysaccharide (LPS)/gamma-interferon (IFN-gamma) stimulated C6 astrocyte cells. In this experiment, 61 compounds were tested, and 36 showed significant suppressive effects of NO production. The results indicate that the following compounds exhibited a dose-dependent suppressive effect of NO production with an IC50 less than 10(-3) M: quercetin, (-)-epigallocatechin gallate, morin, curcumin, apigenin, sesamol, chlorogenic acid, fisetin, (+)-taxifolin, (+)-catechin, ellagic acid, and caffeic acid. Compounds, which reduce NO production at less than 300 ppm, include milk thistle, silymarin, grapenol, and green tea. These results demonstrate a possible value for dietary compounds to inhibit the excessive production of NO.

Radtke J, Linseisen J, Wolfram G
Z Ernahrungswiss; 37(2):190-7 1998 UI: 98363803

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.

Iakovleva LV, Ivakhnenko AK, Buniatian ND
Eksp Klin Farmakol; 61(3):32-4 1998 UI: 98354527

The article presents the material on the study of the cardioprotective effect of ellagic acid on a model of neoepinephrine myocarditis in rats. In doses of 0.5-1 mg/kg ellagic acid causes a marked antioxidant effect. Restores the disturbed myocardial functions. The reference-agent vitamin E (50 mg/kg) yields to ellagic acid as a cardioprotector. The effect of 0.5 mg/kg of ellagic acid was more stable than that of a 1 mg/kg dose. The cardioprotective activity of the drugs under study was determined according to the POL parameters in a myocardial homogenate and blood serum and according to the EEG parameters and the degree of cardiomyocyte cytolysis.

Smith WA, Gupta RC
Mutat Res; 425(1):143-52 1999 UI: 99185178

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.

Smith WA, Freeman JW, Gupta RC
Proc Annu Meet Am Assoc Cancer Res; 38:A2422 1997 UI: 98639422

Over 1500 structurally different chemicals have been identified with potential cancer chemopreventive properties. These properties may be studied by employing short-term tests which provide important mechanistic data and preliminary assessment of the efficacy of these agents. We have previously reported on the use of a cell-free system concomitant with DNA adduct modulation to study more than 30 potential chemopreventive agents. Here we describe the use of a human breast tumor epithelial cell line (MCF-7) to study the effects of 7 chemopreventive agents, N-acetylcysteine, benzylisocyanate, chlorophyllin, curcumin, ellagic acid, genistein and oltipraz on dibenz[a,l]pyrene (DBP)-DNA adduction. Treatment of MCF-7 cells with DBP (10 nM, 24 h) produced one predominant (60%) dA-derived and at least five other dA- or dG-derived adducts (3242 adducts/10(9) N). Pretreatment of cells with oltipraz (15 uM) for 4, 8 or 16 h followed by treatment with DBP resulted in a diminished DNA adduction by 51%, 58% and 78%, respectively. A dose-dependent decrease in DBP DNA adduction by 12%, 32%, 70% and 95% was also observed upon pretreatment of the cells for 20 h with 1.5 uM, 5 uM, 15 uM and 30 uM oltipraz, respectively. Of the other 6 agents tested at 30 uM, chlorophyllin substantially resulted in diminished DBP-DNA adduction (69%) while ellagic acid and genistein were only moderately effective (44% each); benzylisocyanate and N-acetylcysteine were ineffective and curcumin was toxic at this dose. These data suggest that oltipraz and chlorophyllin were highly effective, while genistein and ellagic acid were moderately effective in diminishing DBP-DNA adduction in human breast epithelial cells.

Chen Z, Gundimeda U, Gopalakrishna R
Proc Annu Meet Am Assoc Cancer Res; 38:A1395 1997 UI: 98638395

Ellagic acid is a polyphenol found in fruits and vegetables, and has been shown to have cancer chemopreventive activity. The mechanism of its antitumor promoting activity is not known. Since protein kinase C (PKC) serves as a receptor for tumor promoters as well as can be oxidatively modified by phenolic compounds, we have determined whether ellagic acid can directly regulate this enzyme. When PKC was preincubated with ellagic acid and then assayed with a low (5 uM) or high (100 uM) concentration of ATP, the enzyme was inhibited with an IC50 of 1 and 4 uM, respectively. Detailed studies revealed that this was due to an irreversible inactivation of the enzyme caused by a redox modification. Ellagic acid-iron complex can inactivate PKC without the need for other metals. Both catalytic and regulatory domains of PKC were modified by ellagic as determined by the loss of kinase activity and phorbol ester binding. But the catalytic domain was 3-fold more sensitive. The thiol agents and vitamin C inhibited this inactivation. In JB6 cells, ellagic acid at low (less than 1 to 5 uM) concentrations induced a modification of PKC which was reversed by an endogenous reduction mechanism, while at higher (5 to 25 uM) concentrations, it induced an irreversible inactivation. Taken together these results suggest that the antitumor promoting action of ellagic acid may be mediated in part by inducing a redox modification of PKC.

Hassoun EA, Walter AC, Alsharif NZ, Stohs SJ
Toxicology; 124(1):27-37 1997 UI: 98052346

The ability of vitamin E succinate and ellagic acid to modulate 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced developmental toxicity and oxidative damage in embryonic/fetal and placental tissues was studied in C57BL/6J mice. Vitamin E succinate (100 mg/kg per day) and ellagic acid(6 mg/kg per day) were administered by gavage to groups of pregnant mice on days 10, 11 and 12 of gestation and 40 mg vitamin E succinate/kg or 3 mg ellagic acid/kg on day 13 of gestation. A number of animals from the vitamin E succinate and ellagic acid treated groups also received 30 microg TCDD/kg on day 12 of gestation, 2 h prior to vitamin E succinate or ellagic acid treatment. Groups of treated animals were terminated on day 14 of gestation, and the biomarkers of oxidative stress, including superoxide anion production and the induction of lipid peroxidation and DNA-single strand breaks (SSB), were determined in whole embryonic and placental tissues homogenates. Groups of treated animals were also killed on day 18 of gestation for investigation of the fetotoxic and teratogenic effects as well as effects on the placentae. Vitamin E succinate and ellagic acid significantly decreased TCDD-induced fetal growth retardation fetal death and placental weight reduction, with no significant ameliorating effects on TCDD-induced malformations including cleft palate and hydronephrosis. Vitamin E succinate treatment resulted in decreases of 77-88%, 70-87%, and 21-47% in the production of superoxide anion, lipid peroxidation and DNA-SSB, respectively, in embryonic and placental tissues, while ellagic acid caused 47-98%, 79-93%, and 37-53% decreases, respectively, in these parameters. These results indicate that TCDD-induced fetal death and fetal and placental weight reductions in C57BL/6J mice may be due to oxidative damage induced by TCDD, and ellagic acid and vitamin E succinate provide protection against those effects. Ellagic acid provided better protection than vitamin E succinate against TCDD-induced fetal growth retardation and increases in lipid peroxidation in embryonic and placental tissues.

Hayes MT, Bartley J, Parsons PG, Eaglesham GK, Prakash AS
Biochemistry; 36(35):10646-54 1997 UI: 97419128

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.

Soni KB, Lahiri M, Chackradeo P, Bhide SV, Kuttan R
Cancer Lett; 115(2):129-33 1997 UI: 97293062

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.

Stoner GD, Kresty LA, Carlton PS, Siglin JC, Morse MA
Toxicol Sci; 52(2 Suppl):95-100 1999 UI: 20094292

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.

Wargovich MJ
Cancer Lett; 114(1-2):11-7 1997 UI: 97256404

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.

Smith WA, Arif JM, Gupta RC
Proc Annu Meet Am Assoc Cancer Res; 37:1874 1996 UI: 97609998

We have employed a previously described cell-free system to assess the ability of 27 known or suspected chemopreventive agents to alter activation of the lung carcinogen, BP and the potent mammary carcinogen, DBP. BP or DBP (10 uM) was incubated with DNA (300 ug/ml) in the presence of aroclor 1254-induced rat liver microsomes, with and without chemopreventive agents (150 uM), followed by 32P-postlabeling analysis of purified DNA. BP treatment yielded two major adducts: BPDE-dG and a 9-OH-BP-derived adduct. Treatment with DBP produced two major and five minor, dA- and dG-derived adducts of both anti- and syn-DBP-11,12-diol-13,14-epoxide. Both BP adducts were reduced by greater than or equal to 70% by ellagic acid, oltipraz, genistein, and benzyl isothiocyanate and 40-65% by vitamin H, acetylsalicylic acid, and beta-carotene; BPDE-dG, but not the 9-OH-BP adduct, was inhibited (60-70%) by linoleic acid ethyl ester, biochanin A, indole-3-carboxylic acid, vitamin D3, reduced glutathione, and alpha-tocopherol; and BPDE-dG was inhibited (30-80%), but the 9-OH-BP adduct was enhanced (70-700%) by chlorophyllin, curcumin, butylated hydroxytoluene (BHT), and linoleic acid sodium; or unaffected by ten other compounds. Some of these agents tested also inhibited DBP-DNA adducts: greater than or equal to 75% inhibition by ellagic acid, chlorophyllin, oltipraz, genistein, and benzyl isothiocyanate; 25-40% inhibition by curcumin, BHT, and linoleic acid sodium; or unaffected by N-acetylcysteine. Consistent with our previous observation that ellagic acid inhibits anti-BPDE-dG formation, this agent also inhibited the formation of anti-DBP diolepoxide-DNA adducts. These data support the use of this cell-free system to study mechanism and efficacy of chemopreventive agents.

Harttig U, Hendricks JD, Stoner GD, Bailey GS
Carcinogenesis; 17(11):2403-9 1996 UI: 97122435

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.

Krishnan K, Brenner DE
Gastroenterol Clin North Am; 25(4):821-58 1996 UI: 97120224

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.