bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A38: Is the mycotoxin zearalenone bioactivated to genotoxic metabolites? In vitro evidence for mercapturic acid formation from catechol metabolites
Authors: Hildebrand Andreas , Pfeiffer Erika , Metzler Manfred 
Published: May 2012

Abstract
The Fusarium toxin zearalenone (ZEN) is a frequent contaminant of corn and other grains world-wide and known for its high estrogenic activity. In a NTP carcinogenicity study, ZEN was found to increase the incidence of hepatocellular adenomas in female mice and of pituitary adenomas in both female and male mice. The mechanism of ZEN tumorigenicity is unknown to date and may be related to the hormonal activity. However, the recent disclosure of a novel pathway in the metabolism of ZEN opens up another possibility: ZEN was found to readily undergo aromatic hydroxylation when incubated with hepatic microsomes from humans and various other mammalian species, and two catechol metabolites were unequivocally identified in our laboratory (Pfeiffer et al., Mol. Nutr. Food Res. 53, 1123–1133, 2009). Thus, the phase I metabolism of ZEN resembles that of the steroidal estrogens 17β-estradiol (E2) and estrone (E1), which also form catechol metabolites. There is increasing evidence that these catechol metabolites contribute to the well-established carcinogenicity of E2 and E1 by acting as genotoxins after further activation to quinones (Cavalieri and Rogan, Ann. N. Y. Acad. Sci. 1089, 286–301, 2006; Bolton and Thatcher, Chem. Rev. Toxicol. 21, 93–101, 2008). A similar mechanism is conceivable for the carcinogenicity of ZEN. In order to obtain evidence for the formation of reactive quinone metabolites from ZEN, it was the aim of the present study to trap such quinones as mercapturic acids in microsomal incubations fortified with N-acetylcysteine (NAC).
Incubations (0.4 mL of 0.1 M phosphate buffer pH 7.4) containing human hepatic microsomes (0.4 mg protein), ZEN (0.1 mM) and a NADPH-generating system were conducted for 10 min at 37°C for the formation of catechol metabolites. 0.1 mL of a 40 mM NAC solution in water was then added and incubation continued for another 30 min. Thereafter, 0.5 mL of 0.7 M glycine/HCl buffer pH 1.2 was added and the NAC adducts were extracted with 2 × 0.5 mL ethyl acetate. Analysis of the extract by LC-MS/MS revealed the presence of at least two NAC adducts, which were identified as the N-acetylcysteinyl derivatives of one of the catechol metabolites of ZEN and of its microsomal reductive metabolite alpha-zearalenol by comparison with authentic synthetic standards.
This is the first report to show that reactive quinone metabolites of ZEN are formed in vitro. The toxicological sequelae of this pathway and its in vivo relevance should now be studied.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A38.
Abstract A47: The anti-inflammatory role of statins and lung cancer chemoprevention
Authors: Young Robert , Hopkins Raewyn , Eaton Tam 
Published: May 2012

Abstract
Recently published observational studies involving over 450,000 subjects have shown that statins confer protection from lung cancer with a risk reduction of up to 50% compared to those not taking statins (RR=0.50). Statins are known to inhibit the prenylation of GTPases (Rho, Rac, Ras), intracellular signaling molecules involved in upregulation of genes involved in inflammation, lung matrix remodeling and carcinogenic pathways. This pharmacological effect has been shown to occur at normal therapeutic doses. Lung cancer is thought to result from chronic cigarette exposure but occurs in only 10% of smokers. Chronic obstructive pulmonary disease (COPD), characterised by airflow limitation on lung function testing, is found in approximately 60–90% of lung cancer cases and is the most important risk factor for lung cancer in smokers. COPD results from smoke-induced matrix remodeling involving parenchymal destruction (emphysema), airway fibrosis (small airway narrowing) and epithelial proliferation. These processes are believed to be linked to lung cancer through epithelial-mesenchymal transition (EMT), a process whereby matrix remodeling leads to excessive growth factor mediated stimulation of epithelium and subsequent malignant transformation. These premalignant events are mediated by inflammatory cytokines (notably IL-6 and IL-8) released by bronchial epithelial cells following smoke exposure and whose matrix remodeling effects are mediated by GTPases. Statins are known to inhibit the actions of IL-6 and IL-8 by GTPase inhibition thereby inhibiting the upregulating effects of these cytokines on inflammation. Pre-clinical studies show that inhibition of the GTPases can reduce or even reverse EMT. Studies also show that IL-6 is elevated in lung cancer and that anti-IL-6 activity can prevent carcinogensis. Together these observations suggest that statin therapy could, through down regulation of GTPases, inhibit the initiation of lung cancer through inhibition of the upregulatory effects of inflammatory cytokines such as IL-6. Such a mechanism would explain the possible chemo preventive actions of statins, on the development of lung cancer. Further studies are needed to establish the role of statins in inhibiting EMT and malignant transformation leading to lung cancer.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A47.
Abstract A49: Evidence for gene demethylation in human colon cancer by black raspberries
Authors: Seguin Claire M. , Stoner Kristen , Huang Yi-Wen , Huang Tim , Yang Guang-Yu , Arnold Mark , Martin Edward , Sardo Christine , Stoner Gary D. , Wang Li-Shu 
Published: May 2012

Abstract
Black raspberries (BRBs) exhibit cancer preventative effects in the human colon, in part, by reducing the growth rate and increasing the apoptosis of human colon tumor cells. Recently, we have initiated investigations to determine whether BRBs also cause re-expression of genes in human colon cells that are silenced by aberrant hypermethylation. Cultured human colon cancer cell lines HCT116, Caco2 and SW480, were treated with an anthocyanin-rich (AC) fraction of BRBs every day for five days. AC treatment caused a decreased activity of DNA methyltransferases in a substrate-antibody assay (p&lt;0.05) and a reduction of DNMT1 protein expression. Direct analysis of methylation changes in the promoter region of the suppressor gene p16 (CDKN2A) by Sequenom MassARRAY/EpiTYPER demonstrated a decrease in methylation of all eight p16 promoter CpG units, each unit containing 1–3 CpG sites. All cell lines treated with AC had a significant increase in apoptosis and a decrease in cell proliferation as compared to untreated cells (p&lt; 0.05).
These in vitro observations were confirmed by the examination of normal and tumorous tissue samples taken from 20 colon cancer patients who received daily dietary intervention of freeze-dried BRB powder (60g/day) in drinking water for an average of 3 weeks. DNA from the tissue samples was analyzed by MassARRAY which revealed an overall decrease in p16 methylation in both normal and tumor tissues (p&lt;0.05).
Immunohistochemical analysis of p16 and DNMT1 in the same tissue samples showed that BRB treatment increased p16 expression and decreased DNMT expression (p&lt;0.05), both correlating with decreased methylation of the promoter region of the gene. In addition, the expression levels of Ki-67 and c-myc, both markers of cell proliferation, were reduced in berry treated samples, however, only the reduction in Ki-67 was significant (p&lt;0.05). These data suggest that BRBs are capable of reversing aberrant methylation in both normal and tumorous human colon tissues at tolerable amounts in the diet. This effect appears to be caused by inhibition of DNMT family enzymes, and most likely DNMT1. Supported by NCI grant CA103180 and USDA grant 38903-03560.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A49.
Abstract A51: Comparison of different berry types to prevent chemically induced papilloma development in the rat esophagus
Authors: Chiu Steve , Seguin Claire , Stoner Kristen , Rocha Claudio , Wang Li-Shu , Stoner Gary D. 
Published: May 2012

Abstract
The present study compared the ability of seven different berry types [black and red raspberries, strawberries, blueberries, acai, noni, goji (wolfberry)] to inhibit N-nitrosomethylbenzylamine (NMBA)-induced tumor development in the F344 rat esophagus. These seven berry types have been shown to differ in their relative content of known chemopreventive agents such as anthocyanins, ellagitannins and carotenoids. Each berry type was picked when ripe, freeze-dried under anoxic conditions to prevent decomposition of their chemical components, and ground into a powder. Beginning at 4 weeks of age, 120 F344 rats were injected with NMBA (0.3 mg/kg, 3x/wk for 5 weeks). Control rats (15) were injected with DMSO/water (80:20), the solvent for NMBA. Beginning one week after treatment with carcinogen, individual berry types were administered at 5% of the diet to groups of 15 NMBA-treated rats until the end of the bioassay (35 weeks). At necropsy, the number of esophageal papillomas was enumerated in all groups of rats. No papillomas were seen in control rats treated with DMSO/water. All berry types caused a significant reduction in the number of NMBA-induced papillomas when compared to rats treated with NMBA only. There was no significant difference in the relative ability of the different berry types to reduce tumor incidence, multiplicity or size. Histopathological studies showed that each berry type was about equally effective in preventing the conversion of preneoplastic lesions (dysplasias) to papillomas. These results suggest that the chemopreventive potential of berries for the rat esophagus is not restricted to black raspberries and strawberries as shown previously in our laboratory. They also suggest that berries that vary markedly in their content of anthocyanins, ellagitannins and carotenoids all exhibit chemopreventive potential in the rat esophagus. Supported by NCI grant CA103180 and USDA grant 38903-03560.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A51.
Abstract A55: Targeting of FXR and NHE-1 in prevention of esophageal adenocarcinoma
Authors: Zhang Guihong , Ye Fei , Guan Baoxiang , Xu Xiaochun 
Published: May 2012

Abstract
The incidence of esophageal adenocarcinoma, as one of a few human cancers, has been increasing recently in the United States. Tobacco smoke and low fruit and vegetable consumption are risk factors for both esophageal squamous cell carcinoma and adenocarcinoma, whereas frequent gastroesophageal reflux, overweight, and obesity are linked to the increased incidence of esophageal adenocarcinoma. Our research objective is to understand the molecular mechanisms of esophageal carcinogenesis for developing strategies in its early detection and prevention. In our previous studies, we have associated some of these risk factors with altered gene expression in esophageal cancer. We found that benzo[a]pyrene diol epoxide (BPDE, a carcinogen present in tobacco smoke and environmental pollution) and bile acid (a tumor promoter in gastrointestinal cancer) suppressed expression of RAR-β2 and RRIG1, but induced EGFR, p-ERK, AP-1, and COX-2 expression in esophageal cancer cells. In this study, we have detected expression of FXR and NHE-1, a regulator of intracellular pH, in esophageal cancer tissue specimens and then determined effects of their inhibitors in suppressing growth of esophageal cancer cells. We found that expression of FXR and NHE-1 is increased in esophageal cancer compared to the normal tissues. We also found that inhibition of FXR and NHE-1 activity by using guggulsterone and amiloride can effectively suppress the tumor cell growth and gene expression. Further study will reveal the underlying molecular mechanisms and use FXR and NHE-1 expression as biomarkers for early detection or prognosis of esophageal cancer.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A55.
Abstract A57: High-dose resveratrol modulates drug and carcinogen metabolizing enzymes in a healthy volunteer study
Authors: Chow H-H Sherry , Garland Linda , Hsu Chiu-Hsieh , Vining Donna , Chew Wade , Miller Jessica A. , Perloff Marjorie , Crowell James A. , Alberts David S. 
Published: May 2012

Abstract
Purpose: Resveratrol (RES) or 3, 4′, 5-trihydroxystilbene has been shown to inhibit carcinogenesis by affecting various molecular events in the initiation, promotion and progression stages. The cancer chemopreventive activity of RES has been demonstrated in vivo in a wide variety of tumors including skin, mammary, gastrointestinal, and liver cancer models. Modulation of Phase I and Phase II enzymes has been suggested to be one of the mechanisms responsible for the cancer preventive effect of RES. We conducted a clinical study to determine the effect of pharmacological doses of RES on drug and carcinogen metabolizing enzymes.
Methods: Forty-two healthy volunteers underwent baseline assessment of Phase I and Phase II enzymes. A cocktail of cytochrome P450 (CYP) metabolic probe drugs, including caffeine, dextromethorphan, losartan, and buspirone, were administered to assess the activity of CYP1A2, 2D6, 2C9, and 3A4, respectively. Blood and urine samples were collected for 8 hours after probe drug administration to determine parent probe drug and metabolite concentrations for measurements of CYP enzyme activities. Blood lymphocyte glutathione S-transferase (GST) activity and GST-π level, and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess Phase II enzymes. After the baseline evaluation, study participants took 1 gm of RES once daily for 4 wks. Enzyme assessment was repeated upon intervention completion.
Results: RES intervention was found to suppress the activity of CYP3A4, 2D6, and 2C9. The geometric mean change of the activity index of CPY3A4, 2D6, and 2C9 was 33% (p = 0.01), 70% (p = 0.01), and 171% (p &lt; 0.0001), respectively. CYP1A2 activity was induced; the geometric mean change of the activity index was 16% (p = 0.005). The overall GST and UGT1A1 activity index were minimally affected by the intervention while an induction of GST-π level (84%, p = 0.002) and UGT1A1 activity index (20%, p = 0.0089) was observed in individuals with baseline enzyme level/activity in the lowest tertile.
Conclusion: We conclude that high doses of RES administration may modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which RES inhibits carcinogenesis. However, high doses of RES administration may lead to clinically relevant metabolic drug interactions. Further clinical studies are needed to determine whether lower doses of RES could be used to achieve cancer preventive activities. (Supported by N01CN35158 from the National Cancer Institute, Division of Cancer Prevention)
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A57.
Abstract A6: Ethnic differences in risk of lung cancer associated with repair capacity for tobacco carcinogen-induced DNA adduct
Authors: Wang Li-E , Spitz Margaret R. , Qiao Yawei , Dong Qiong , Amos Christopher I. , Wei Qingyi 
Published: May 2012

Abstract
Lung cancer is initiated by tobacco carcinogens-induced DNA damage, such as DNA adducts caused by benzo[a]pyrene diol epoxide (BPDE). These adducts can be removed by an efficient nucleotide excision repair. We have previously reported that DNA repair capacity (DRC) measured by the host-cell reactivation assay is associated with risk of lung cancer in non-Hispanic whites. In the recent analysis with larger sample sizes including minorities, we found that the suboptimal DRC remains associated with increased risk of lung cancer in 1730 cases and 1683 controls of non-Hispanic whites. The mean values of DRC were 8.37% ± 2.8% (SD) in the cases vs. 9.04% ± 3.1% in the controls (P &lt; 0.0001). The odds ratio (OR) was 1.42 (95% confidence interval [CI], 1.24 – 1.64) after adjustment for age, sex, pack-years of smoking, family history of cancer, and other assay-related covariates. The similar results and risk trend have been also found in 127 Mexican-American patients with lung cancer and 176 cancer-free controls with a mean DRC of 8.38% ± 2.7% in the cases vs. 9.04% ± 3.3% in the controls, and an adjusted OR of 1.67 (95% CI, 1.00 – 2.78), although the difference in mean DRC values was borderline significant (P = 0.056) because of the relatively small sample size. However, this difference in DRC for tobacco carcinogen-induced DNA adducts was not significant in 327 African-American patients with lung cancer and 325 cancer-free controls. The mean values of DRC were 8.90% ± 3.1% in the cases vs. 8.66% ± 2.8% in the controls (P = 0.301). The adjusted OR was 0.99 (95% CI, 0.70 – 1.39). The DRC level in African-American controls was non-significantly lower than other ethnic controls (P = 0.144); however, African-American patients had significantly higher DRC than non-Hispanic white patients and Mexican-Americans patients (P = 0.053). The results further confirmed that low DRC is associated with increased risk of lung cancer in non-Hispanic whites and also provided the evidence of this association in Mexican Americans. These findings help us understand the ethnic differences in the development of lung cancer.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A6.
Abstract A60: Epigenetic modifications of huntingtin-related genes by dietary components for the prevention and treatment of breast cancer
Authors: Abdolmaleky Sayed Hamid , Eskandari Mohammad , Li Linglin , Zhou Jin-Rong 
Published: May 2012

Abstract
Huntingtin protein (Htt) interplays with a large numbers of proteins and participates in diverse cellular pathways. Wide variety of Htt binding partners have been identified, including the Htt-Interacting protein-1 (HIP1) and Htt-associated protein-1 (HAP1). Htt has been shown pro-apoptotic activity, and malfunctioning of Htt may result in cell outgrowth. HIP1 is involved in endocytosis and receptor trafficking and introduced as an oncoprotein. An altered expression of HIP1 has been reported in various cancers including breast cancer. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Recent evidence supports a role of HAP1 in micro-tubule-dependent organells transport, but its role in cancer development and progression has not been studied. We propose that the HAP1 and HIP1 may serve as a pair of “Ying-Yang” modulators on the Htt functions and that the Htt-HAP1-HIP1 pathway may play an important role in the development and progression of breast cancer. We further propose that dietary/nutritional components that target this pathway may have chemopreventive effects on breast cancer. The objective of this study was to evaluate the differential expression and epigenetic modification patterns of Htt pathway related genes in normal and cancerous breast cells treated by dietary active components.
Human breast cancer cells were treated with dietary components known to prevent cancer cell growth and the effects of these components on HAP1, HIP1 and HTT expressions and promoter DNA methylations were investigated by using real-time PCR, Methylation Specific PCR (MSP) and bisulfite sequencing. HAP1 gene was silenced in several breast cancer cell lines including MCF7, MDA-MB231, MB453, SKBR3 and in much lower extent in immortalized MCF10A cells, but not in normal human mammary epithelial cell line (HMEC). Epigenetic analysis for Htt, HIP1 and HAP1 showed severe HAP1 promoter DNA hypermethylation in breast cancer cell lines, but not in HMEC. When the cells were treated with 5-AZaC (a DNA demethylating agent) and butyrate (a HDAC inhibitor), we found that 5-AZaC treatment significantly increased HAP1 expression by over 100 times, but butyrate had little effects. Treatment of the cells with dietary active compounds, sulfuraphane, EGCG, oridonin, tanshinone 2A and cryptotanshinone increased expression of HAP1 and HTT genes and decreased expression of HIP1 gene in HMEC, more significantly in cancer cell lines MCF7 and MB453. Preliminary studies indicate that these dietary components acted through modulation of HAP1 promoter methylation and further experiments are taking place to construct HTT and HAP-1 expressing plasmids for further in vitro and in vivo gene function studies.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A60.
Abstract A62: Increased histone acetylation, but no inhibition of HDAC activity, by kale sprout intervention in a human prostate cancer xenograft model
Authors: Kim Jung-Hyun , Bähr Marion , Wagner Julia , De Nicola Gina , Rüfer Corinna , Jung Manfred , Iori Renato , Gerhäuser Clarissa 
Published: May 2012

Abstract
Cruciferous vegetable consumption has been associated with a reduced risk of prostate cancer. These vegetables such as broccoli and kale are rich in glucosinolates, which are converted to isothiocyanates (ITCs) by myrosinase. ITCs have cancer preventive potential through various mechanisms including anti-proliferative effects. ITC metabolites have been recently identified as inhibitors of histone deacetylases (HDAC), which have the potential to turn on epigenetically silenced genes, leading to cell cycle arrest and apoptosis.
In the present study we investigated the effect of kale sprouts commercially available as a food supplement to inhibit the growth of human LNCaP prostate cancer cells in a xenograft model. We were interested whether kale sprout intervention would affect histone acetylation and in studying underlining mechanisms, e.g. HDACs and histone acetyltransferases (HAT). LNCaP human prostate cancer cells were injected to male nude Balb/c mice (10 per group). Mice were fed with either regular rodent chow or chow supplemented with 20% kale sprouts (containing about 60 µmol glucosinolates per 5 g chow consumed daily, together with active myrosinase) from a week before cell injection until sacrifice. 7.5 weeks after injection, tumor tissue was collected.
Kale sprout intervention did not significantly inhibit tumor growth in the xenograft model. However, global acetylation levels of histone H4 detected by Western blotting were increased in the kale sprout-treated group, whereas acetylated histone H3 levels were not significantly changed. The increase of H4 lysine 5, 8, 12 and 16 acetylation was individually confirmed. Among them, acetylated H4 K12 was most abundant. Even though global acetylation of H3 did not change, acetylated H3K9 was significantly increased. Unexpectedly, HDAC activity in nuclear extracts of tumor tissue determined by using ZMAL substrate was not significantly inhibited in tumor tissue by kale sprout intervention. Also, protein expression of HDAC family members HDAC1-5 was not changed overall, although HDAC 5 expression was reduced while HDAC2 expression was increased. Instead, kale sprout treatment significantly increased mRNA levels of PCAF and CBP quantified by qRT-PCR, by 36% and 23%, respectively, in tumor tissue (p&lt;0.001), which may contribute to increased H4 acetylation.
Taken together, our results indicate that dietary consumption of kale sprouts increased global acetylation of histone H4 in LNCaP prostate cancer xenograft model, possibly by induction of HAT expression rather than inhibition of HDAC activity.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A62.