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Background: Epidemiologic research suggests that increased cancer risk due to chronic arsenic exposure persists for several decades even after the exposure has terminated. Observational studies suggest that antioxidants exert a protective effect on arsenical skin lesions and cancers among those chronically exposed to arsenic through drinking water. This study reports on the design, methods and baseline analyses from the Bangladesh Vitamin E and Selenium Trial (BEST), a population-based chemoprevention study conducted among adults in Bangladesh with visible arsenic toxicity., Materials and Methods: Bangladesh Vitamin E and Selenium Trial is a 2 × 2 full factorial, double-blind, randomized controlled trial of 7000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of nonmelanoma skin cancer., Results: In cross-sectional analyses, we observed significant associations of skin lesion severity with male gender (female prevalence odds ratio (POR) = 0.87; 95% CI = 0.79-0.96), older age (aged 36-45 years, POR = 1.27; 95% CI = 1.13-1.42; aged 46-55 years, POR = 1.44; 95% CI = 1.27-1.64 and aged 56-65 years, POR = 1.50; 95% CI = 1.26-1.78 compared with aged 25-35 years), hypertension (POR = 1.29; 95% CI = 1.08-1.55), diabetes (POR = 2.13; 95% CI = 1.32-3.46), asthma (POR = 1.55; 95% CI = 1.03-2.32) and peptic ulcer disease (POR = 1.20; 95% CI = 1.07-1.35)., Conclusions: We report novel associations between arsenical skin lesions with several common chronic diseases. With the rapidly increasing burden of preventable cancers in developing countries, efficient and feasible chemoprevention study designs and approaches, such as employed in BEST, may prove both timely and potentially beneficial in conceiving cancer chemoprevention trials in Bangladesh and beyond., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

We have shown that, in contrast to selenomethionine (SeMet) or selenite, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) exert prostate cancer (PCa) inhibitory effect in preclinical models. Here we investigated the prostate proteome signatures of mice treated with each selenium (Se) form for hypothesis generation concerning their potential in vivo molecular targets and cancer risk modification. Nude mice bearing subcutaneous PC-3 xenografts were treated daily with each Se form (3 mg Se/kg) orally for 45 days. Five prostates were pooled from each group. Their proteomes were profiled by LC-MS/MS with iTRAQ labeling. Of the 1,088 proteins identified, 72 were significantly modulated by one or more Se forms. MSeA and MSeC each induced separate sets of tumor suppressor proteins and suppressed different onco-proteins. Proteins induced by selenite and shared with MSeC were related to energy metabolism (e.g., fatty-acid synthase), and those induced by SeMet included vimentin and heat-shock protein-70, favoring cancer growth. While proteome changes induced by MSeA were associated with PCa risk reduction, desirable risk-reducing signatures induced by MSeC were counterbalanced by risk-promoting patterns shared with selenite and SeMet. We propose that the balance of oncogenic vs. suppressor protein patterns in the prostate may impact the direction of PCa risk modification by a given selenium.

This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that, among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine downregulated interleukin (IL)-2 by 9% (P = 0.04), whereas celecoxib downregulated IL-7 by 11% (P = 0.006) and upregulated IL-13 by 17% (P = 0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall [odds ratio (OR), 1.47; P = 0.03] and among those with mild dysplasia at t0 (OR, 2.53; P = 0.001). An increase in IL-2 tertile from baseline to t10 was also nonsignificantly associated with worsening dysplasia for all participants (OR, 1.32; P = 0.098) and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR, 2.0; P = 0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR, 2.52; P = 0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, whereas celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10-month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect in reducing the levels of IL-2., (2010 AACR.)

Methylselenol has been implicated as an active anticancer selenium (Se) metabolite. However, its in vivo efficacy against prostate cancer (PCa) has yet to be established. Here, we evaluated the growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human PCa xenografts in athymic nude mice. Each Se was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed serum, liver and tumor Se content to confirm supplementation status and apoptosis indices and tumor microvessel density for association with antitumor efficacy. Furthermore, we analyzed lymphocyte DNA integrity to detect genotoxic effect of Se treatments. The data show that MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor Se retention than in the SeMet-treated mice. Selenite treatment increased DNA single-strand breaks in peripheral lymphocytes, whereas the other Se forms did not. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and cleaved caspase-3 indices (apoptosis) from MSeC-treated tumors were higher than tumors from control mice or MSeA-treated mice, whereas the microvessel density index was lower in tumors from MSeA-treated mice. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body wt. In summary, our data demonstrated superior in vivo growth inhibitory efficacy of MSeA over SeMet and selenite, against two human PCa xenograft models without the genotoxic property of selenite.

Background: Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations., Results: Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium., Conclusions: Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer.

This is a report of research efforts underway at the Arizona Cancer Center. These efforts build upon Larry Clark's unanticipated clinical prevention trial results: those results indicated that 200 microg/day of selenium in selenized yeast decreased prostate cancer risk by almost 60%. The trials underway address various phases of the possible preventive activity of selenium. The first of these, for men who are suspected to have prostate cancer but who have had a biopsy revealing no evidence of cancer, will test the ability of selenium to prevent the development of clinical prostate cancer. The second is for men with high-grade prostatic intraepithelial neoplasia; the trial will test whether selenium will prevent the development of prostatic cancer in this high-risk group. The third trial is for men who have been diagnosed with prostate cancer and are scheduled for prostatectomy: the trial is designed to test whether evidence of selenium-linked changes can be identified in the tissue removed at prostatectomy. The fourth trial is for men who have been diagnosed with prostate cancer but who have chosen neither surgery nor irradiation; this trial will evaluate whether treatment with selenium will inhibit the progress of prostate cancer. Together, these trials will provide important information as to the prostate cancer chemopreventive potential of selenium.