[Liujunzi Decoction treats 4NQO-induced esophageal cancer in mice: a study based on serum metabolomics].

This study aims to explore the mechanism of Liujunzi Decoction in the treatment of 4-nitroquinoline-N-oxide(4NQO)-induced esophageal cancer in mice. One hundred mice of 35-45 days were randomized into blank, model, and low-, medium-, and high-concentration(18.2, 36.4, and 54.6 g·kg~(-1), respectively) Liujunzi Decoction groups. The mice in other groups except the blank group had free access to the water containing 100 µg·mL~(-1) 4NQO for 16 weeks for the modeling of esophageal cancer. The mice in the Liujunzi Decoction groups were fed with the diets supplemented with corresponding concentrations of Liujunzi Decoction. The body weight and organ weights were weighed for the calculation of organ indexes. The pathological changes of the esophageal tissue were observed by hematoxylin-eosin(HE) staining. Ultra performance liquid chromatography-mass spectrometry(UPLC-MS/MS) was employed to collect metabolites from mouse serum samples, screen out potential biomarkers, and predict related metabolic pathways. Compared with the blank group, the model group showed decreased spleen and stomach indexes and increased lung, esophagus, and kidney indexes. Compared with the model group, Liujunzi Decoction groups had no significant changes in the organ indexes. The HE staining results showed that Liujunzi Decoction inhibited the invasive growth and cancerization of the esophageal cancer cells. A total of 9 potential biomarkers of Liujunzi Decoction in treating esophageal cancer were screened out in this study, which were urocanic acid, 1-oleoylglycerophosphoserine, 11-deoxy prostaglandin E1, Leu-Glu-Lys-Glu,(±) 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid, ureidosuccinic acid,(2R)-2,4-dihydroxy-3,3-dimethylbutanoic acid, kynurenic acid, and bicyclo prostaglandin E2, which were mainly involved in histidine, pyrimidine, alanine, aspartate, glutamate, pantothenate and tryptophan metabolism and coenzyme A biosynthesis. In summary, Liujunzi Decoction may exert the therapeutic effect on the 4NQO-induced esophageal cancer in mice by regu-lating the amino acid metabolism, inflammation, and immune function.

Improvement of postoperative quality of life in patients with esophageal squamous cell carcinoma: does tea consumption have a role?

BACKGROUND: To investigate the effect of tea consumption on the improvement of postoperative quality of life in male patients with esophageal squamous cell carcinoma (ESCC). METHODS: The quality of life information of 290 male patients with ESCC was collected. The time to deterioration and the number of events in each area of quality of life was calculated by time-to-deterioration (TTD) model. The association between postoperative tea drinking and postoperative quality of life in male ESCC patients was investigated using the Cox proportional risk model. RESULTS: Postoperative tea-drinking patients experienced delayed TTD in multiple domains, including general health, physical, role, emotional, and cognitive function, fatigue, nausea and vomiting, dyspnea, loss of appetite, constipation, diarrhea, eating problems, difficulty swallowing, choking while swallowing saliva, dry mouth, taste difficulties, coughing, and speech problems. The multivariate Cox regression analysis showed that drinking tea after surgery improved quality of life, including physical function (HR = 0.722, 95% CI: 0.559-0.933), role function (HR = 0.740, 95% CI: 0.557-0.983), eating problems (HR = 0.718, 95% CI: 0.537-0.960), odynophagia (HR = 0.682, 95% CI: 0.492-0.945), trouble swallowing saliva (HR = 0.624, 95% CI: 0.444-0.877), coughing (HR = 0.627, 95% CI: 0.442-0.889) and speech problems (HR = 0.631, 95% CI: 0.441-0.903). Furthermore, the improvement was more significant in patients who drank tea before surgery and continued to drink tea after surgery. CONCLUSIONS: Postoperative tea drinking had a positive effect on delay in clinical deterioration and improvements in multiple functions and symptoms associated with ESCC in men.

Meta-Analysis of the Association between Asbestos Exposure and Esophageal Cancer.

BACKGROUND: We conducted a meta-analysis to quantitatively assess the association between asbestos exposure and esophageal cancer. METHODS: We systematically collected articles from three electronic databases and calculated the pooled standardized mortality rate (SMR) from the meta-analysis. Subgroup analysis according to the type of asbestos exposure, follow-up years, sample size, industry classification, sex, and high-dose exposure was conducted. RESULTS: From 242 studies, 34 cohort studies were included in our meta-analysis. Pooled SMR was positively associated with asbestos exposure and esophageal cancer (pooled SMR = 1.28; 95% confidence interval (CI) 1.19-1.38, p < 0.00001). In the subgroup analysis, (1) chrysolite, (2) four groups with follow-up over ten years, (3) the textile industry and shipyard, (4) both male and female, and (5) eight studies on highest asbestos exposure, all the subgroups showed significantly increased pooled SMRs. CONCLUSION: Asbestos exposure was significantly and positively associated with esophageal cancer, especially chrysolite. Considering the long latency period, we suggest that patients should be followed up for cancer, including esophageal cancer, for over ten years.

Abrogation of esophageal carcinoma development in miR-31 knockout rats.

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.

Methanolic extract of Potentilla fulgens root and its ethyl-acetate fraction delays the process of carcinogenesis in mice.

People of north-eastern states of India consume raw areca-nut (RAN) and lime which could lead to oral, esophageal and gastric cancers. However, the incidence of these cancers are significantly lesser in those who consume pieces of Potentilla fulgens root along with RAN. Since evaluation of anticancer role, if any, of P. fulgens on RAN-mediated genetic alterations in human is difficult because of other compounding factors, this study was undertaken in mice to focus on gastric carcinogenesis since ad libitum administration of RAN extract with lime in drinking water induced stomach cancer due to greater exposure of its lining. A total of 160 mice were used at different time points and either methanol extract of P. fulgens roots (PRE) or mixture of four compounds of ethyl-acetate fraction (EA-mixture) was mixed with mice feed. Histological studies revealed that RAN + lime induced cancer in all the mice and interestingly only 20% developed cancer when PRE/EA-mixture was provided along with RAN + lime. Higher frequency of precocious anaphase and over expression of p53 and Securin genes were significantly reduced by PRE/EA-mixture. Thus PRE/EA-mixture mitigates the RAN-induced tumor-initiating process in stomach by maintaining expression of tumor suppressor and check-point genes under control.

Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells.

Tobacco in its smoke and smokeless form are major risk factors for esophageal squamous cell carcinoma (ESCC). However, molecular alterations associated with smokeless tobacco exposure are poorly understood. In the Indian subcontinent, tobacco is predominantly consumed in chewing form. An understanding of molecular alterations associated with chewing tobacco exposure is vital for identifying molecular markers and potential targets. We developed an in vitro cellular model by exposing non-transformed esophageal epithelial cells to chewing tobacco over an eight-month period. Chronic exposure to chewing tobacco led to increase in cell proliferation, invasive ability and anchorage independent growth, indicating cell transformation. Molecular alterations associated with chewing tobacco exposure were characterized by carrying out exome sequencing and quantitative proteomic profiling of parental cells and chewing tobacco exposed cells. Quantitative proteomic analysis revealed increased expression of cancer stem cell markers in tobacco treated cells. In addition, tobacco exposed cells showed the Oxidative Phosphorylation (OXPHOS) phenotype with decreased expression of enzymes associated with glycolytic pathway and increased expression of a large number of mitochondrial proteins involved in electron transport chain as well as enzymes of the tricarboxylic acid (TCA) cycle. Electron micrographs revealed increase in number and size of mitochondria. Based on these observations, we propose that chronic exposure of esophageal epithelial cells to tobacco leads to cancer stem cell-like phenotype. These cells show the characteristic OXPHOS phenotype, which can be potentially targeted as a therapeutic strategy.

p-Hydroxylcinnamaldehyde slows the progression of 4NQO-induced oesophageal tumourigenesis via the RhoA-MAPK signaling pathway.

p-Hydroxylcinnamaldehyde isolated from the Cochinchina momordica seed (CMSP) has been identified to inhibit growth and metastasis in oesophageal squamous cell carcinoma (ESCC) by inducing differentiation. The aim of the present study was to evaluate the effect and underlying mechanism of CMSP on 4-nitroquinoline 1-oxide (4NQO)-induced oesophageal tumourigenesis. In the present study, a mouse model of oesophageal preneoplastic lesions was established by providing 4NQO-containing drinking water to C57BL/6 mice. The effect of CMSP on tumourigenesis induced by the chemical mutagen and the effect of CMSP on immune function were investigated. The results showed that the incidence and pathological stage of atypical hyperplasia in oesophageal tissues were significantly reduced in CMSP-treated mice compared with untreated mice. Immunohistochemistry and pull-down assay results revealed that the expression levels of p-ERK1/2, p-SAPK/JNK, and GTP-RhoA were significantly decreased in the oesophageal tissue of CMSP-treated mice. In addition, the proportions of CD4+ T cells, CD8+ T cells, and NK cells were increased, while the proportion of CD4+ CD25+ regulatory T cells (Tregs) was decreased, in the peripheral blood of CMSP-treated mice. These results indicated that CMSP could hamper 4NQO-induced oesophageal tumourigenesis by regulating the RhoA-ERK/JNK signaling pathway and promoting immune system function, thus providing a new potential strategy for treating preneoplastic lesions of the oesophagus.

Comparative oesophageal cancer risk assessment of hot beverage consumption (coffee, mate and tea): the margin of exposure of PAH vs very hot temperatures.

BACKGROUND: Consumption of very hot (> 65 °C) beverages is probably associated with increased risk of oesophageal cancer. First associations were reported for yerba mate and it was initially believed that high content of polycyclic aromatic hydrocarbons (PAH) might explain the risk. Later research on other beverage groups such as tea and coffee, which are also consumed very hot, found associations with increased risk of oesophageal cancer as well. The risk may therefore not be inherent in any compound contained in mate, but due to temperature. The aim of this study was to quantitatively assess the risk of PAH in comparison with the risk of the temperature effect using the margin of exposure (MOE) methodology. METHODS: The human dietary benzo[a]pyrene (BaP) and PAH4 (sum of benzo[a]pyrene, benzo[a]anthracene, chrysene, and benzo[b]fluoranthene) exposure through consumption of coffee, mate, and tea was estimated. The oesophageal cancer risk assessment for both PAH and temperature was conducted using the MOE approach. RESULTS: Considering differences in the transfer of the PAH from the leaves of mate and tea or from the ground coffee to the infusion, and considering the different preparation methods, exposures may vary considerably. The average individual exposure in µg/kg bw/day arising from consumption of 1 cup (0.2 L) of infusion was highest for mate (2.85E-04 BaP and 7.22E-04 PAH4). The average per capita exposure in µg/kg bw/day was as follows: coffee (4.21E-04 BaP, 4.15E-03 PAH4), mate (4.26E-03 BaP, 2.45E-02 PAH4), and tea (8.03E-04 BaP, 4.98E-03 PAH4). For all individual and population-based exposure scenarios, the average MOE for BaP and PAH4 was > 100,000 independent of beverage type. MOE values in this magnitude are considered as a very low risk. On the contrary, the MOE for the temperature effect was estimated as < 1 for very hot drinking temperatures, corroborating epidemiological observations about a probable oesophageal cancer risk caused by this behaviour. CONCLUSIONS: The temperature effect but not PAH exposure may pose an oesophageal cancer risk. Consumer education on risks associated with consumption of 'very hot' beverages and policy measures to threshold serving temperatures should be discussed.

Black raspberries demethylate Sfrp4, a WNT pathway antagonist, in rat esophageal squamous cell papilloma.

Aberrant methylation of DNA is a common event in the development of cancers, including squamous cell carcinoma (SCC) of the human esophagus. In the present study, we determined: (a) whether aberrant DNA methylation also occurs in the development of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus, a model of human esophageal SCC; and (b) if so, whether dietary black raspberries (BRBs) are capable of preventing this aberrant DNA methylation. A diet containing 5% BRBs inhibited the development of NMBA-induced tumors in the rat esophagus. This inhibition was associated with reduced mRNA levels of the DNA methyltransferases, Dnmt1 and Dnmt3b, in both dysplastic lesions and in papillomas of the esophagus. In addition, promoter methylation of Sfrp4, a WNT pathway antagonist, was significantly reduced by the berry diet, and this was associated with decreased nuclear localization of ß-CATENIN and reduced expression of c-MYC protein in NMBA-treated esophagi. Decreased promoter methylation of Sfrp4 correlated with decreased expression of Dmnt3b and, ultimately, with increased Sfrp4 mRNA expression. This suggests that epigenetic alterations in NMBA-induced rat esophageal tumorigenesis recapitulate epigenetic events in human esophageal SCC, and that BRBs could be useful in preventing the aberrant DNA methylation involved in the development of human esophageal SCC. © 2015 Wiley Periodicals, Inc.

Rhizoma Paridis Saponins Suppresses Tumor Growth in a Rat Model of N-Nitrosomethylbenzylamine-Induced Esophageal Cancer by Inhibiting Cyclooxygenases-2 Pathway.

Rhizoma Paridis Saponins (RPS), a natural compound purified from Rhizoma Paridis, has been found to inhibit cancer growth in vitro and in animal models of cancer. However, its effects on esophageal cancer remain unexplored. The purpose of this study was to investigate the effects of RPS on tumor growth in a rat model of esophageal cancer and the molecular mechanism underlying the effects. A rat model of esophageal cancer was established by subcutaneous injection of N-nitrosomethylbenzylamine (NMBA, 1 mg/kg) for 10 weeks. RPS (350 mg/kg or 100 mg/kg) was administered by oral gavage once daily for 24 weeks starting at the first NMBA injection. RPS significantly reduced the size and number of tumors in the esophagus of rats exposed to NMBA and inhibited the viability, migration, and invasion of esophageal cancer cells EC9706 and KYSE150 in a dose dependent manner (all P < 0.01). Flow cytometry revealed that RPS induced apoptosis and cell cycle G2/M arrest in the esophageal cancer cells. The expression of cyclooxygenases-2 (COX-2) and Cyclin D1 in rat esophageal tissues and the esophageal cancer cells were also significantly reduced by RPS (all P < 0.01). Consistently, RPS also significantly decreased the release of prostaglandin E2, a downstream molecule of COX-2, in a dose-dependent manner (P < 0.01). Our study suggests that RPS inhibit esophageal cancer development by promoting apoptosis and cell cycle arrest and inhibiting the COX-2 pathway. RPS might be a promising therapeutic agent for esophageal cancer.

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling.

The aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO-induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC.

Hydroferrate fluid, MRN-100, provides protection against chemical-induced gastric and esophageal cancer in Wistar rats.

In the current study, we examined the protective effect of hydroferrate fluid MRN-100 against the carcinogen methylnitronitrosoguanidine (MNNG)-induced gastric and esophageal cancer in rats. MRN-100 is an iron-based compound composed of bivalent and trivalent ferrates. At 33 weeks post treatment with MNNG, rats were killed and examined for the histopathology of esophagus and stomach; liver, spleen, and total body weight; and antioxidant levels in the blood and stomach tissues. Results showed that 17/20 (85%) gastroesophageal tissues from carcinogen MNNG-treated rats developed dysplasia and cancer, as compared to 8/20 (40%) rats treated with MNNG plus MRN-100. In addition, MRN-100 exerted an antioxidant effect in both the blood and stomach tissues by increasing levels of GSH, antioxidant enzymes SOD, CAT, and GPx, and total antioxidant capacity (TAC) level. This was accompanied by a reduction in the total free-radical and malondialdehyde levels. Furthermore, MRN-100 protected against body and organ weight loss. Thus, MRN-100 exhibited significant cancer chemopreventive activity by protecting tissues against oxidative damage in rats, which may suggest its effectiveness as an adjuvant for the treatment of gastric/esophageal carcinoma.

[Effect of vitamin E and selenium deficiency on esophageal tumorigenesis and its oxidative stress mechanism].

OBJECTIVE: To explore the effect of vitamin E (VE) and selenium (Se) deficiency on esophageal tumorigenesis and its oxidative stress mechanism. METHODS: 110 male F344 rats were randomly divided into 3 groups: VE/Se deficient group (group A), VE/Se normal group (group B) and control group (group C). Animals in group A and group B were subcutaneously injected with N-nitrosomethylbenzylamine (NMBzA) at the dosage of 0.35 mg/kg BW, 3 times per week for 5 weeks. Control group was given the solvent 20% DMSO as negative control. Animals in group A were fed with low-VE/Se diet (46IU/kg VE, 0.05 mg/kg Se), animals in group B and C were fed with normal diet (80IU/kg VE, 0.15 mg/kg Se). Animals were sacrificed to perform macroscopic observation and pathologic inspection at the 25th week of the experiment. Plasma VE level was determined by high-performance liquid chromatography, and Se level was determined by fluorescence method. Cell proliferation and DNA damage in esophagus were detected through immunohistochemistry of BrdU and 8-OH-dG, respectively. Glutathione peroxidase (GPX) and glutathione transferase (GST) activities in plasma, esophagus and liver were analyzed by using test kits. RESULTS: VE/Se levels of group A were significantly lower than those of group B, the later were slightly lower than those of group C. Visible tumor incidence, tumor multiplicity and pathologic lesions in group A were all significantly more than those in group B. Comparing with group B, cell proliferation and 8-OH-dG levels were also significantly increased in group A. GPX and GST activities in plasma, esophagus and liver of group A were significantly higher than those of group B. CONCLUSION: Vitamin E and selenium deficiency significantly promoted the NMBzA-induced esophageal tumorigenesis. Oxidative stress and DNA damage may be one of the critical routes by which NMBzA induces carcinogenesis in rat esophagus.

The role of selenium and selected trace elements in the etiology of esophageal cancer in high risk Golestan province of Iran.

Selenium (Se) deficiency is reported by some authors to be an important factor in the etiology of esophageal cancer (EC) in the Golestan province of Iran. In order to further investigate the role of Se and selected trace elements in the occurrence of EC disease, 663 samples including 206 cultivated soils, 247 sediments, 45 loess deposits and 165 grain samples from 45 villages in the Golestan province of Iran were collected and analyzed. Villages in the study area were classified into 2 groups according to the EC incidence in the local population. The results of this study demonstrate that, contrary to the expected trend, total Se concentrations in soil, grain, sediment, and loess samples increase from the low to the high EC areas suggesting that Se deficiency does not play a major role in the etiology of EC. On the other hand, antimony (Sb), and strontium (Sr) content in soil, grain, loess, and sediment samples is much higher in the high esophageal cancer area, which may be a significant factor. Total zinc (Zn) concentrations in soil, grain, loess, and sediment samples decrease from the low to the high cancer areas. Therefore, Zn deficiency may be a significant factor in EC incidence rate in the Golestan province.

Esophageal cancer: associated factors with special reference to the Kashmir Valley.

Esophageal cancer is one of the most common cancers worldwide. It is a multifactorial disease, and no single agent has been identified so far as the sole cause of the cancer. Many factors like smoking, the consumption of alcohol, fungal-contaminated, spicy and various nitrosamine-containing food stuffs and hot beverages, nutritional deficiency of some vitamins like ß-carotene, vitamin A, C and E and minerals like zinc, selenium and molybdenum, the use of opium, HPV infection and various genetic factors have been found associated with the occurrence of the disease worldwide. Wide geographic differences and substantial changes in the incidence of esophageal cancer occurring over time have been suggested. Among the risk factors in India, betel quid chewing carries a relatively high risk. High incidences in Kashmir have been associated with the consumption of hot salted tea, sun-dried, smoked foods, tobacco in the form of hukka and various genetic factors. The exact cause of esophageal squamous cell carcinoma is unknown. Much work has been carried out on the role of various environmental factors, gene mutations, and polymorphisms worldwide, including Kashmir. Although the Kashmir valley is present on the border of the 'high risk esophageal cancer belt' and esophageal squamous cell carcinoma represents the most commonly occurring malignancy in Kashmir, the amount of information available on various associated factors is still very little as there is a paucity of various epidemiological and molecular studies being carried out in this field.

Time-selective chemoprevention of vitamin E and selenium on esophageal carcinogenesis in rats: the possible role of nuclear factor kappaB signaling pathway.

Previous human intervention trial demonstrated that vitamin E (Ve) and selenium (Se) supplementation decreased esophageal cancer deaths among younger participants, but may have no effect or produce an opposite effect among older ones. In our study, we intended to mimic this human nutritional trial to determine the chemopreventive effects of Ve/Se supplementation at the early or late stage of esophageal carcinogenesis in rats. Esophageal squamous cell carcinoma (ESCC) was induced in Fischer 344 rats with N-nitrosomethylbenzylamine (NMBzA, 0.35 mg/kg BW, s.c., three times per week for 5 weeks). The rats were maintained on a modified AIN-93M diet with low levels of Ve/Se or supplemented with high levels of Ve/Se at different stages. At Week 25, the number and volume of visible tumors, the numbers of dysplasia and ESCC were significantly lower in rats of supplementation during the early stage (Group C) or during the entire experimental period (Group E), but not during the late stage (Group D). Ve/Se supplementation at the early stage also significantly decreased cell proliferation, nuclear factor kappaB (NFκB) activation, protein and mRNA expression of cyclooxygenase 2 and 5-lipoxygenase and biosynthesis of prostaglandin E2 and leukotriene B4 during the carcinogenesis of rat esophagus. Our results demonstrated that the chemopreventive efficacy of Ve/Se supplementation on NMBzA-induced esophageal cancer is time selective and that supplementation during the early stage is clearly effective but probably ineffective during the late stage of carcinogenesis. NFκB signaling pathway activation and aberrant arachidonic acid metabolism might be the underlying mechanism.

Relevance of drug metabolizing enzyme activity modulation by tea polyphenols in the inhibition of esophageal tumorigenesis.

Tea is a popular, socially accepted, drink that is enjoyed by millions of people. A growing body of evidence suggests that moderate consumption of tea may protect against several forms of cancer. It is also known that bioactivation of precarcinogens and detoxification of ultimate carcinogens is carried out mainly by drug metabolizing enzymes such as cytochrome P450 (CYP). The present study investigates the effect of tea consumption on modulating CYP and phase II conjugating enzymes, and their association in the chemopreventive effect against esophageal tumorigenesis using both in vitro and in vivo techniques. Female Wistar rats were given aqueous solutions (2% w/v) of six different teas, standard green tea extract (GTE) (0.5% w/v), and dandelion tea (2% w/v) as the sole source of fluid for two weeks prior to and during the entire period of tumour induction (12 weeks). Animals were gavaged with 0.5 mg/kg N-nitrosomethylbenzylamine (NMBA) twice weekly for 12 weeks for esophageal tumor induction and the activities of different CYP isoforms and phase II enzymes were determined in the liver microsomes or cytosols. GTE, green tea and Dandelion tea caused decrease in tumour multiplication, tumour size and tumour volume; however, none of these tea preparations altered tumour incidence. No appreciable changes in drug metabolizing enzyme activity were observed in the treatment groups. Thus, the modulations in the activities of CYP 1A1/ 1A2 and CYP2E enzymes, by pre-treatment with green and dandelion teas, observed in our earlier experiments, seem to be compensated by the tumor inducing agent, NMBA. The balance between phase I carcinogen-activating enzymes and phase II detoxifying enzymes could be important in determining the risk of developing chemically-induced cancer and the present study in conjunction with the previous observations suggest a possible role of drug metabolizing enzymes in the anticancer effect of tea.

Mechanistic basis for the chemopreventive effects of black raspberries at a late stage of rat esophageal carcinogenesis.

The present study used a postinitiation protocol to investigate molecular mechanisms by which black raspberries (BRBs) influence the late stages of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in rats. F344 rats were injected with NMBA and then fed either control diet or a diet containing 5% BRB powder. Control rats were injected with DMSO/water (20:80), the vehicle for NMBA. Esophagi from control, NMBA- and NMBA + BRB-treated rats were collected at 35 wk for histopathological, molecular, and immunohistochemical analyses. Treatment with 5% BRBs reduced the number of dysplastic lesions and the number and size of esophageal papillomas in NMBA-treated rats. When compared to esophagi from control rats, NMBA treatment led to the differential expression of 4807 genes in preneoplastic esophagus (PE) and 17 846 genes in esophageal papillomas. Dietary BRBs modulated 626 of the 4807 differentially expressed genes in PE and 625 of the 17 846 differentially expressed genes in esophageal papillomas towards normal levels of expression. In both PE and in papillomas, BRBs modulated the mRNA expression of genes associated with carbohydrate and lipid metabolism, cell proliferation and death, and inflammation. In these same tissues, BRBs modulated the expression of proteins associated with proliferation, apoptosis, inflammation, angiogenesis, and both cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Interestingly, matrix metalloproteinases involved in tissue invasion and metastasis, and proteins associated with cell-cell adhesion, were also modulated by BRBs. This is the first report of the effects of berries on the expression of genes associated with the late stages of rat esophageal carcinogenesis.

Chemopreventive effects of early-stage and late-stage supplementation of vitamin E and selenium on esophageal carcinogenesis in rats maintained on a low vitamin E/selenium diet.

Low vitamin E and selenium (Ve/Se) nutritional status is known to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). A previous human intervention trial demonstrated that Ve/Se supplementation decreased the occurrence of esophageal cancer death among younger participants but not among older ones. In this study, we intended to mimic this human nutritional status to determine the chemopreventive effects of Ve/Se supplementation at the early or late stage of esophageal carcinogenesis in rats maintained on a low Ve/Se diet. ESCC was induced in F344 rats with N-nitrosomethylbenzylamine (NMBzA) (0.35 mg/kg body wt, subcutaneously, three times per week for 5 weeks). The rats were maintained on a modified AIN-93M diet with low levels of Ve/Se or supplementation to the normal level by using the AIN-93M diet. At Week 25, the numbers of visible tumors and ESCC were significantly lower in rats on AIN-93M diet during the entire experimental period (Group D) or during the early stage (Group B) but not during the late stage (Group C). Ve/Se supplementation (switching from the low Ve/Se diet to the AIN-93M diet) also decreased cell proliferation, angiogenesis, 8-hydroxy-2'-deoxyguanosine, biosynthesis of prostaglandin E2 and leukotriene B4, expression of cyclooxygenase 2 and 5-lipoxygenase in the esophagus. Our results demonstrated that Ve/Se supplementation inhibited NMBzA-induced esophageal carcinogenesis in rats on low Ve/Se diet, and supplementation during the early stage is more effective than during the late stage of carcinogenesis.