Search

Cancer chemopreventive activity of sulforaphane has been predominantly associated with its ability to induce phase II detoxification enzymes. In the present study, novel targets of sulforaphane were identified and characterized using a proteomics approach. Two-dimensional gel electrophoresis and mass spectrometry were used to produce protein profiles of human colon adenocarcinoma Caco-2 cells treated with 5 μmol/L sulforaphane for 48 h and control cells (0.05% DMSO). Gel comparisons showed the down-regulation to undetectable level of the serotonin receptor 5-HT3 after sulforaphane treatment. In addition, Aldo-keto reductase and d-dopachrome decarboxylase were also differentially expressed in control and treated cell extracts. To elucidate two-dimensional gel findings, the neurotransmitter receptors 5-HT3A, 5-HT1A, 5-HT2C, and the serotonin reuptake transporter were analyzed using Western blotting. Results showed a decrease of neurotransmitter receptors in a dose-dependent manner after sulforaphane treatment. Moreover, after exposure of Caco-2 cells to sulforaphane, nicotinic acetylcholine receptor protein level was increased. These findings suggested a potential effect of sulforaphane on serotonin release. Activation of neurotransmitter receptors followed by initiation of cyclic AMP signaling might be crucial events in colon carcinoma progression. Thus, the effect of sulforaphane may help to elucidate signaling pathways serotonin-mediated in colon cancer and lead to development of potential novel therapeutic agents. [Cancer Res 2008;68(13):5487–91]

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a recent randomized controlled trial, the Polyp Prevention Trial, a higher intake of one sub-class, flavonols, was significantly associated with a 76% reduced risk of recurrent advanced adenoma. Cohort studies that have examined the association between flavonoid intake and risk of colorectal cancer (CRC) have yielded inconsistent results, but most previous studies only evaluated habitual intake of a limited number of subclasses and there is growing evidence for differential effects depending on subtle difference in structure between the sub-classes Objective: To examine whether higher habitual dietary intake of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones and polymers) are associated with lower risk of CRC. Methods: Using data from validated food frequency questionnaires administered every four years and an updated USDA flavonoid food composition database flavonoid intakes were calculated for 73,666 participants from the Nurses’ Health Study I, and for 32,059 participants from the Health Professionals Follow-up Study. Results: During 16 years of follow-up, 1,405 colorectal cancer cases (652 in men, 753 in women) were identified. Intakes of total flavonoids and subclasses were not associated with risk of CRC (hazard ratios (95% confidence interval) multivariable adjusted for age, smoking before age 30, family history of colorectal cancer, history of endoscopy, aspirin use, body mass index, physical activity, postmenopausal hormone use in women, alcohol consumption, intake of total energy, calcium and vitamin D; highest vs. lowest quintile: total flavonoids, men: 0.97 (0.75-1.26), women: 1.00 (0.80-1.26); flavonols, men: 0.98 (0.76-1.26), women: 1.21 (0.96-1.52); flavones, men: 0.86 (0.67-1.11), women: 0.90 (0.72-1.13); flavanones, men: 0.98 (0.75-1.28), women: 1.00 (0.80-1.26); flavan-3-ols, men: 1.00 (0.78-1.29), women: 0.96 (0.76-1.21); anthocyanins, men: 0.89 (0.69-1.15), women: 1.25 (0.98-1.60); polymers, men: 0.92 (0.71-1.18), women: 0.88 (0.69-1.11)). Conclusion: Our findings do not provide support for the hypothesis that a higher intake of flavonoids or any specific sub-class decrease risk of CRC. Citation Format: Katharina Nimptsch, Xuehong Zhang, Edward Giovannucci, Aedin Cassidy, Éilis J. O'Reilly, Tobias Pischon, Eric B. Rimm, Jennifer Lin, Walter C. Willett, Charles S. Fuchs, Kana Wu. Habitual intake of total flavonoids and flavonoid subclasses and risk of colorectal cancer in men and women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4820. doi:10.1158/1538-7445.AM2013-4820

Currently, there is significant interest in the field of diet-gene interactions and the mechanisms by which food compounds regulate gene expression through epigenetic events to modify cancer susceptibility. Evidence from epidemiological, in vivo and in vitro studies have suggested that the chemopreventive effect of cruciferous vegetables is attributed to the glucosinolate break-down products, isothiocyanates (ITCs). Similarly, selenium (Se) is an integral part of many cellular antioxidant enzymes and like isothiocyanates has been inversely associated with the incidence of cancer as a result of influencing multiple pathways in the development of cancer. However, their efficacy might depend on the chemical form in which they are administered. We therefore examined the synergistic effect of two forms of selenium, selenium-methylselenocysteine (Se-MSC) and selenite (200nM) with ITCs (6µM) such as iberin and sulforaphane on the expression of antioxidant selenoenzymes such as thioredoxin-reductase (TrxR1) and gastrointestinal glutathione peroxidise (GI-GPx) in an in vitro model using Caco-2 cells. Our preliminary results suggest that the simultaneous addition of Se-MSC and iberin significantly induced TrxR1 and GI-GPx mRNA and protein expression more than either compound alone by ∼6 fold (p In addition to the antioxidant protection provided by these selenoproteins, DNA methylation is essential for normal development, but aberrant DNA methylation patterns are a hallmark of most cancers and include global DNA hypomethylation, region-specific hypermethylation and increased DNA methyltransferases (DNMTs) activity. We therefore also examined the impact of Se and ITCs on DNA methylation, specifically examining factors modulating DNMT1, 3A, 3B expression and methylation of the LINE-1 retrotransposon, a surrogate marker of global DNA methylation. Caco-2 cells were treated with Se-MSC and selenite using 0.2, 0.5, 1, 2 and 5µM, in addition to the ITCs (6µM) after 5 and 10 days of treatment. Our initial data suggests that methylation of LINE-1 in the control group was indeed low (55%) and treatment of cells with DNMT inhibitor 5-aza-2 deoxycytidine resulted in a 45% reduction in LINE-1 methylation as expected. Unexpectedly, none of the food compounds or dose used in this study modified significantly the methylation status of LINE-1. Interestingly, although the methylation levels of this marker remain unchanged, the mRNA expression of the DNMTs showed the tendency to decrease, following the same pattern in the different treatments and time courses albeit with small differences, which suggests that both de novo and maintenance DNMTs work in concert to create and propagate methylation patterns. However, only DNMT3B showed a significant reduction of 35 and 38% after 10 days of treatment with Se-MSC (500nM) (p=0.04) and selenite (1µM) (p=0.035) respectively. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1896.