The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor.

The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[α]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression.

Chemopreventive effects of the juice of Vitis coignetiae Pulliat on two-stage mouse skin carcinogenesis.

Our study revealed the inhibitory effect of Vitis coignetiae Pulliat, known as Yamabudo in Japan, at the stages of multi-step carcinogenesis. The juice of Vitis coignetiae (Y-grape juice) was antimutagenic toward dimethylbenzo[a]anthracene (DMBA), aflatoxin B1, and benzo[a]pyrene in the Ames test. The Y-grape juice was also antigenotoxic in the micronucleus test using HepG2 cells toward DMBA and aflatoxin B1. Topical and oral administration of the Y-grape juice to mice inhibited the induction of inflammation of 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical and oral administration of the Y-grape juice significantly decreased the incidence and mean number of tumors in mice skin with the 2-stage tumorigenesis protocol. To elucidate the mechanisms underlying the antiinflammatory and antitumor promotion activity of the Y-grape juice, the effect of Y-grape juice on cyclooxygenase-2 (COX-2) activity in mouse ear treated with TPA was studied. Both topical and oral application of the Y-grape juice inhibited the TPA-induced increase in COX-2 activity. Caftaric acid, isolated and identified from the Y-grape juice, was antimutagenic toward DMBA and prevented TPA-induced inflammation in mice, suggesting caftaric acid participates in chemopreventive effect/activities of Y-grape juice.

Antioxidative effects of the spice cardamom against non-melanoma skin cancer by modulating nuclear factor erythroid-2-related factor 2 and NF-κB signalling pathways.

The role of dietary factors in inhibiting or delaying the development of non-melanoma skin cancer (NMSC) has been investigated for many years. Cardamom, which is a dietary phytoproduct, has been commonly used in cuisines for flavour and has numerous health benefits, such as improving digestion and stimulating metabolism and having antitumorigenic effects. We have investigated the efficacy of dietary cardamom against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin papillomatogenesis in Swiss albino mice that closely resembles human NMSC. Mice were grouped into normal wild type (untreated), vehicle-treated (acetone), carcinogen-treated (DMBA), and DMBA and cardamom-treated (DMBA+CARD) to delineate the role of cardamom against DMBA-induced papillomatogenesis. Oral administration of cardamom to DMBA-treated mice up-regulated the phase II detoxification enzymes, such as glutathione-S-transferase and glutathione peroxidase, probably via activation of nuclear factor erythroid-2-related factor 2 transcription factor in 'DMBA+CARD' mice. Furthermore, reduced glutathione, glutathione reductase, superoxide dismutase and catalase were also up-regulated by cardamom in the same 'DMBA+CARD' group of mice compared with DMBA-treated mice. Cardamom ingestion in DMBA-treated mice blocked NF-κB activation and down-regulated cyclo-oxygenase-2 expression. As a consequence, both the size and the number of skin papillomas generated on the skin due to the DMBA treatment were reduced in the 'DMBA+CARD' group. Thus, the results from the present study suggest that cardamom has a potential to become a pivotal chemopreventive agent to prevent papillomagenesis on the skin.

Metabolic transformation of DMBA-induced carcinogenesis and inhibitory effect of salvianolic acid b and breviscapine treatment.

Oral cancer typically develops from hyperplasia through dysplasia to carcinoma with a multistep process of carcinogenesis involving genetic alterations resulting in aberrant cellular appearance, deregulated cell growth, and carcinoma. The metabolic transformation during the process of oral carcinogenesis and its implications for cancer therapy have not been extensively investigated. Here, we report a metabonomic study on a classical model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced oral carcinogenesis in hamsters to delineate characteristic metabolic transformation during the carcinogenesis using gas chromatography time-of-flight mass spectrometry (GC-TOF MS). Salvianolic acid B (Sal-B), isolated from Salvia miltiorrhiza Bge, and Breviscapine, a flavonoid isolated from Herba Erigerontis, were used to treat the hamsters exposed to DMBA to investigate the molecular mechanism of the inhibitory effect of the two agents on oral carcinogenesis. The dynamic changes of serum metabolic profiles indicated that both Sal-B and Breviscapine were able to attenuate DMBA-induced metabolic perturbation, which is consistent with the histopathological findings that Sal-B and Breviscapine significantly decreased the squamous cell carcinoma (SCC) incidence in the two treatment groups. Significant alterations of key metabolic pathways, including elevated glutaminolysis and glycolysis, and decreased cholesterol and myo-inositol metabolism, were observed in the DMBA-induced model group, which were attenuated or normalized by Sal-B or Breviscapine treatment. Elevated inflammation and tumor angiogenesis at gene and metabolite expression levels were also observed in DMBA-induced oral dysplasia and SCC but were attenuated or normalized by Sal-B and Breviscapine along with significantly decreased incidences of SCC formation.

Mixtures of Uncaria and Tabebuia extracts are potentially chemopreventive in CBA/Ca mice: a long-term experiment.

A long-term experimental animal model was developed by our research group for the evaluation of potential chemopreventive effects. The inhibitory effects of agents on carcinogen (7,12-dimethylbenz[a]anthracene (DMBA) induced molecular epidemiological biomarkers, in this case the expression of key onco/suppressor genes were investigated. The expression pattern of c-myc, Ha-ras, Bcl-2, K-ras protooncogene and p53 tumour suppressor gene were studied to elucidate early carcinogenic and potential chemopreventive effects. The consumption of so-called Claw of Dragon tea (CoD™ tea) containing the bark of Uncaria guianensis, Cat's Claw (Uncaria sp. U. tomentosa) and Palmer trumpet-tree (Tabebuia sp. T. avellanedae) was able to decrease the DMBA-induced onco/suppressor gene overexpression in a short-term animal experiment. In a following study CBA/Ca mice were treated with 20 mg/kg bw DMBA intraperitoneally (i.p.) and the expression patterns of onco/suppressor genes were examined at several time intervals. According to the examined gene expression patterns in this long-term experiment the chemopreventive effect of CoD™ tea consumption could be confirmed.

Calcium glucarate inhibits DMBA-induced oral carcinogenesis in the hamster: histomorphometric evaluation.

BACKGROUND: Calcium glucarate (CGT) is a promising chemopreventive agent. This study evaluated the in vivo efficacy of CGT in preventing 7,12-dimethylbenz(alpha) anthracene (DMBA)-induced oral carcinogenesis in the hamster. Matherials and Methods: Seventy-six Syrian hamsters were used, divided into four groups: group 1, untreated animals; 2, CGT controls; 3, DMBA-treated; 4, DMBA- and CGT-treated. Hamsters were painted three times weekly with 0.5% solution of DMBA and were fed a diet supplemented with CGT (64 mmol/kg, 2%). Animals were sacrificed at week 9 and 12 and pathology and histomorphometric analyses were performed. RESULTS: At week 9, four dysplastic lesions and six carcinomas were identified in group 3 while only three dysplasias and five carcinomas were detected in group 4. At week 12, five animals of group 3 displayed a dysplasia, which was only detected in one animal of group 4. Squamous carcinomas were identified in all animals of both group 3 and 4. However, in group 3 four of the animals displayed multifocal lesions and carcinomas displayed histological features indicative of increased aggressiveness. CONCLUSION: The results obtained suggest that CGT can exert an inhibitory effect on oral carcinogenesis in tha hamster and that further studies are warranted to evaluate its potential use as a chemopreventive agent in humans.

Skin tumor promotion by argemone oil/alkaloid in mice: evidence for enhanced cell proliferation, ornithine decarboxylase, cyclooxygenase-2 and activation of MAPK/NF-kappaB pathway.

Consumption of argemone oil (AO) contaminated edible oil causes "Epidemic Dropsy". Previously, we have shown that AO and isolated sanguinarine possess genotoxicity and skin tumor initiating activity. Here, we evaluate tumor-promoting potential of AO/sanguinarine alkaloid and investigate the molecular mechanisms involved therein. Single topical application of AO (50-400 microl/mouse) or sanguinarine alkaloid (1.5-12.0 micromol/mouse) afforded significant increase in (i) ornithine decarboxylase (ODC) activity, (ii) uptake of [(3)H]-thymidine in DNA, (iii) cyclooxygenase-2 (COX-2), proliferating cell nuclear antigen (PCNA) and ODC protein expressions, (iv) phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-jun-N-terminal kinase (JNK)1/2 and p38 mitogen-activated protein (MAP) kinases, (v) increased NF-kappaB activation and (vi) no significant increase in dark basal keratinocytes. Subsequently, when AO and sanguinarine alkaloid was tested either as complete or stage I or stage II tumor promoter in 7, 12-dimethyl benz(a)anthracene (DMBA)-initiated mice, there was enhanced tumor incidence, tumor body burden and higher % of mice with tumors, when AO (0.1 ml) or isolated sanguinarine (1.5 micromol) was tested as stage II tumor promoter. However, no tumors were found when AO or sanguinarine alkaloid was tested either as complete or stage I tumor promoter. These results indicate that AO/ sanguinarine alkaloid possesses tumor-promoting potential at stage II level involving MAPK/NF-kappaB pathway.

Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis.

Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00, 16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00 h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell proliferation in the buccal mucosa.

Chemomodulatory action of Foeniculum vulgare (Fennel) on skin and forestomach papillomagenesis, enzymes associated with xenobiotic metabolism and antioxidant status in murine model system.

The chemopreventive effect of different doses of test diet of Foeniculum vulgare Mill (Fennel) seeds was examined on DMBA-induced skin and B(a)P-induced forestomach papillomagenesis in Swiss albino mice. To the best of our knowledge, this is the first report of Fennel seeds exhibiting a significant reduction in the skin and the forestomach tumor incidence and tumor multiplicity as compared to the control group. Further, biochemical assays showed a significant increase in the content/activities of phase I enzymes especially in the case of 6% test diet. A concomitant increase in the activities of the phase II enzymes were observed with all the doses of test diet under study. A significant enhancement in the activities of antioxidant enzymes were observed especially at 4% and 6% test diets of Fennel. Glyoxalase I activity and the content of reduced glutathione were significantly elevated. Expectedly, the levels of peroxidative damage along with lactate dehydrogenase activity, exhibited a significant reduction at all three doses of test diets. These findings were indicative of chemopreventive potential of Fennel against carcinogenesis.

Protective role of withaferin-A on 7,12-dimethylbenz(a)anthracene-induced genotoxicity in bone marrow of Syrian golden hamsters.

The present study has investigated the antigenotoxic effect of withaferin-A, a steroidal lactone obtained from the roots and leaves of Withania somnifera, in 7,12-dimethylbenz(a)anthracene (DMBA)-induced genotoxicity. Measurement of the frequency of micronucleated polychromatic erythrocytes (MnPCEs) and chromosomal aberrations is used as cytogenetic endpoints. A single intraperitoneal injection of DMBA (30 mg/kg b.w.) to golden Syrian hamsters resulted in marked elevation in the frequency of MnPCEs and aberrations in the chromosomal structure. Hamsters pretreated with withaferin-A intraperitonealy 2 h before the injection of DMBA, significantly reduced the frequency of MnPCEs and chromosomal aberrations such as chromosomal break, gap, minute, and fragment. Our results thus demonstrated the antigenotoxic effect of withaferin-A in DMBA-induced genotoxicity in the bone marrow of golden Syrian hamsters.

Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice.

We investigated the effects of the chronic administration of hesperetin on the activation of the antioxidant defence system in mice in which oxidative stress had been induced by 7,12-dimethylbenz(a)anthracene (DMBA). Mice were divided randomly into three treatment groups. Hesperetin was administered orally to two of the three groups at 10 and 50 mg/kg body weight for 5 weeks. Subsequently, each group was subdivided randomly into DMBA-treated and untreated groups. The DMBA-treated groups were intragastrically administered a dose of 34 mg/kg BW in corn oil vehicle twice a week for 2 weeks. The TBARS value showed a tendency to decrease following hesperetin treatment; these decreases were significantly greater in the DMBA-treated than the untreated groups. Hesperetin significantly decreased the carbonyl content at the high dose in both DMBA-treated and untreated mice. Catalase and SOD activity were increased by hesperetin; this increase was more pronounced in DMBA-treated than untreated mice. Catalase, Mn-SOD, and CuZn-SOD expression analyses supported these results. Although the GSH-px and GR activity were little affected, hesperetin treatment significantly increased the GSH/GSSG ratio in the DMBA-treated group in a dose-dependent manner. These results suggest that hesperetin shows antioxidant activity and plays a protective role against DMBA-induced oxidative stress.

Inhibition of 7,12-dimethylbenz[a]anthracene induced mouse skin carcinogenesis by Artemisia capillaris.

Anticarcinogenic activity of medicinal herbs (Artemisia capillaris, Taxus cuspidata, Anthriscus sylveatris, and Curcuma longa) was examined for 7,12-dimethylbenz[a]anthracene (DMBA)-induced mouse skin carcinogenesis. Four types of solvent fractions (hexane, chloroform, ethyl acetate, and butanol) were prepared from the methanolic extract of medicinal herbs. The cytotoxicity and anticarcinogenic activities of solvent fractions were examined for mouse leukemia L1210 cancer cells and for female ICR mouse epidermal carcinogenesis induced by DMBA, respectively. The chloroform fraction of Artemisia capillaris, Taxus cuspidata, and Anthriscus sylveatris was more toxic to L1210 cells than other solvent fractions. The chloroform fraction of Artemisia capillaris markedly reduced the number of tumors/mouse and tumor incidence relative to that of other medicinal herbs tested. Major active chemical constituents in the chloroform fraction of Artemisia capillaries were found to be camphor, 1-borneol, coumarin, and achillin when analyzed by TLC and GC-MS. These results suggest that Artemisia capillaris was the most effective anticarcinogenic medicinal herb for DMBA-induced mouse epidermal carcinogenesis among 4 medicinal herbs tested, and the effect might be attributed to chemical compounds of camphor, 1-borneol, coumarin, and achillin.

Induction of apoptosis by 9,10-dimethyl-1,2-benzanthracene in cultured preovulatory rat follicles is preceded by a rise in reactive oxygen species and is prevented by glutathione.

The polycyclic aromatic hydrocarbon (PAH) 9,10-dimethyl-1,2-benzanthracene (DMBA) destroys primordial, primary, and secondary ovarian follicles in rodents, but its effects on antral follicles have received limited attention. PAHs are metabolized to reactive species, some of which can undergo redox cycling to generate reactive oxygen species (ROS). We previously showed that ROS initiate apoptosis in preovulatory follicles cultured without gonadotropin support and that glutathione (GSH) depletion induces apoptosis in the presence of gonadotropins. In the present study, we tested the hypothesis that DMBA induces apoptosis in preovulatory follicles, which is mediated by ROS and prevented by GSH. Preovulatory follicles were isolated from ovaries of 25-day-old rats 48 h after the injection of 10 IU of eCG and were cultured with DMBA in the presence of FSH for 2 to 48 h. DMBA induced granulosa cell (GC) and theca cell (TC) apoptosis at 48 h, as judged by TUNEL and activated caspase-3 immunostaining. DMBA treatment also increased the numbers of GCs and TCs that immunostained for the proapoptotic protein BAX. Follicular ROS levels were significantly increased in DMBA-treated follicles at 12, 24, and 48 h. GSH supplementation protected against and GSH depletion enhanced the induction of apoptosis in GCs and TCs by DMBA. These findings suggest that GSH is a critical protective mechanism against DMBA-induced apoptosis in antral follicles and that ROS generation may mediate DMBA-induced GC apoptosis.

Lack of chemopreventive effects of alpha-eleostearic acid on 7,12-dimethylbenz[a]anthracene (DMBA) and 1,2-dimethylhydrazine (DMH)-induced mammary and colon carcinogenesis in female Sprague-Dawley rats.

alpha-Eleostearic acid is one of the conjugated linolenic acids from tung oil, which is obtained from the seeds of Aleurites fordii. The effects of dietary alpha-eleostearic acid (18:3, n-5) on the post-initiation period of 7,12-dimethylbenz[a]anthracene (DMBA) and 1,2-dimethylhydrazine (DMH)-induced mammary and colon carcinogenesis were examined using female Sprague-Dawley (SD) rats. For initiation, rats were given subcutaneous injections of 40mg/kg body weight (5 times) and 20mg/kg body weight (3 times) of DMH during the age of 6-8 weeks and a single intragastric administration of 50mg/kg body weight of DMBA at 9 weeks. Then, the animals were treated with 0%, 0.01%, 0.1% or 1.0% alpha-eleostearic acid for 34 weeks. Control rats received the basal diet alone or 1.0% alpha-eleostearic acid without prior initiation treatment. All surviving animals were killed at week 37 of the experiment. There were no statistically significant alterations in any of the parameters for either mammary or colon tumors. These results thus indicate that alpha-eleostearic acid does not exert clear modification effects on DMBA and DMH-induced mammary and colon carcinogenesis, at least under the present experimental conditions.

Green tea polyphenol epigallocatechin-3 gallate (EGCG) affects gene expression of breast cancer cells transformed by the carcinogen 7,12-dimethylbenz[a]anthracene.

Since the 1980s, the incidence of late-onset breast cancer has been increasing in the United States. Known risk factors, such as genetic modifications, have been estimated to account for approximately 5 to 10% of breast cancer cases, and these tend to be early onset. Thus, exposure to and bioaccumulation of ubiquitous environmental chemicals, such as polycyclic aromatic hydrocarbons (PAHs), have been proposed to play a role in this increased incidence. Treatment of female Sprague-Dawley rats with a single dose of the PAH 7,12-dimethylbenz[a]anthracene (DMBA) induces mammary tumors in approximately 90 to 95% of test animals. We showed previously that female rats treated with DMBA and given green tea as drinking fluid displayed significantly decreased mammary tumor burden and invasiveness and a significantly increased latency to first tumor. Here we used cDNA microarray analysis to elucidate the effects of the green tea polyphenol epigallocatechin-3 gallate (EGCG) on the gene expression profile in a DMBA-transformed breast cancer cell line. RNA was isolated, in quadruplicate, from D3-1 cells treated with 60 mug/mL EGCG for 2, 7, or 24 h and subjected to analysis. Semiquantitative RT-PCR and Northern blot analyses confirmed the changes in the expression of 12 representative genes seen in the microarray experiments. Overall, our results documented EGCG-altered expression of genes involved in nuclear and cytoplasmic transport, transformation, redox signaling, response to hypoxia, and PAHs.

Toxicity induced by the chemical carcinogen 7,12-dimethylbenz[a]anthracene and the protective effects of selenium in Wistar rats.

7,12-Dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), has been used extensively as a tool to initiate mammary carcinogenesis and subsequent chemoprevention. On the other hand, selenium (Se) is potentially useful in oncology because this element possesses anticarcinogenic and chemopreventive properties. Se-containing enzymes such as glutathione peroxidase (GPx) play an important role in PAH metabolism and detoxification. In this study, rats were administered a single, oral dose of DMBA (12 mg). In the Se group, rats received 20 microg Se daily via gavage, starting 2 wk before the DMBA administration and continued for 1 wk. One hundred twenty days after DMBA administration the rats were sacrificed and toxicity was evaluated using histopathological and biochemical criteria. Five rats (30%) died in the DMBA group within the study period, whereas no death occurred in the DMBA-Se-treated group. Malignant tumor frequency was 33% in the DMBA group, while no malignant tumors occurred in the DMBA-Se-treated group. Some inflammatory changes rather than epithelial changes were found upon histopathological examination. GPx activity and blood urea nitrogen levels were higher and kidney GST activity was lower in the DMBA-Se-treated group compared to DMBA alone. In conclusion, Se appears to be effective in preventing some of the adverse effects associated with DMBA.

Antioxidant potential of black tea against 7,12-dimethylbenz(a)anthracene- induced oxidative stress in Swiss albino mice.

Oxygen free radicals and related reactive species have been implicated in the etiology of many diseases, such as atherosclerosis, neurodegenerative disorders, and cancer. Antioxidant enzymes exist in cells to protect against the effects of these free radicals and other oxygen-derived species, which are produced during the oxidative stress. Tea (Camellia sinensis) is the most commonly consumed beverage worldwide. Both green and black tea are known to possess many pharmacological properties, including antioxidant, antipyretic, antibacterial, and antineoplastic effects. In the present study, the preventive effects of black tea extract (BTE) was evaluated in Swiss albino mice against 7,12-dimethyl benz(a)anthracene (DMBA)-induced oxidative stress. The animals were given 0.5%, 1%, and 1.5% BTE as the sole source of drinking solution for 1 week prior to the administration of DMBA, which was given orally as a single dose of 50 mg/kg body weight. At the end of the study period, the liver, kidney, and prostate tissues were dissected out for the determination of antioxidant enzyme levels (catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase), and lipid peroxidation. A dose-dependent protective effect of BTE against DMBA-induced depletion in enzymes activity was observed in all three tissues examined. Similarly, a significant dose-dependent inhibition of the lipid peroxidation caused by DMBA was observed in the BTE-administered animals in all three tissues examined. Our results revealed that BTE provides protection against oxidative damage induced by xenobiotics.

Ichthyotoxic and anticarcinogenic effects of triterpenoids from Sandoricum koetjape bark.

After bioassay-guided fractionation of the extract from Sandoricum koetjape bark, which exhibited significant toxicity to killifish (Oryzias latipes), two ichthyotoxic triterpenoids were isolated and characterized as koetjapic acid and 3-oxo-olean-12-en-29-oic acid. These constituents, along with non-toxic katonic acid, had a remarkable inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), which is a preliminary in vitro screening method for possible anti-tumor-promoting agents. Of the triterpenoids active in vitro, koetjapic acid appears to be a promising cancer chemopreventive agent, since it significantly delayed tumor promotion in two-stage mouse skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene and promoted by TPA.

Regulation of hazardous exposure by protective exposure: modulation of phase II detoxification and lipid peroxidation by Camellia sinensis and Swertia chirata.

Many natural compounds are now known to have a modulatory role on physiological functions and biotransformation reactions involved in the detoxification process, thereby affording protection from cytotoxic, genotoxic, and metabolic actions of environmental toxicants. As part of a programme on evaluation of food, beverage, and traditional medicinal plants for their anticarcinogenic activity, their effects on detoxification enzymes were also studied. The present report deals with Camellia sinensis and Swertia chirata. The effect of water infusions as well as crude and purified components of these plants on glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) was analyzed in mice that were exposed to the chemical carcinogen DMBA. All the four enzymes were found to be activated in different degrees following treatment. The effect of Theaflavin, a component of black tea, was highly significant. The activation of the enzymes was accompanied by significant reduction in lipid peroxidation. The observation suggest the chemopreventive potential of both Camellia sinensis and Swertia chirata.

Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot.

Our previous studies identified the extract of Beta vulgaris (beetroot), commercially also known as betanin, as a potent cancer chemopreventive agent in both in vitro Epstein-Barr early antigen activation assay and in an in vivo two-stage mouse lung and skin carcinogenesis. To explore this issue further, we have now investigated its cancer chemopreventive potentials in three different chemical carcinogen initiation-promotion experimental tumor models in mice. Following tumor initiation with 390 nmol of 7,12-dimethylbenz(a)anthracene (DMBA) in 100 microl of acetone, the mouse skin tumor promotion with 3430 J/m(2) of ultraviolet light-B (UV-B) as well as splenomegaly was significantly inhibited by oral administration of 0.0025% betanin. At the same dose, betanin also afforded significant protection in the mouse skin cancer model following the topical application of 390 nmol of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) in 100 microl of acetone and promoted by topical administration of 1.7 nmol of 12-O-tetradecanoylphorbol-13-acetate (TPA). In the two-stage model of hepatocarcinogenesis in mice with N-nitrosodiethylamine (DEN, 30 mg/kg) as the initiator and phenobarbital as the promoter, oral administration of 0.0025% betanin also showed a very significant inhibition of both the incidence and multiplicity of the liver tumors. These findings along with our initial reports suggest that betanin which is a regularly consumed natural product colorant is an effective cancer chemopreventive agent in mice. The most interesting observation is that the cancer chemopreventive effect was exhibited at a very low dose used in the study and thus indicating that beetroot warrants more attention for possible human applications in the control of malignancy.