Search

Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1 ppm selenium as selenium-enriched milk protein, or combination of 1 ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ß-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0.01; the combination also had a significant additive inhibition effect on all tumor endpoints, the effect of the combination diet on tumor incidence, multiplicity and size was greater than selenium or green tea alone, P<0.01. Rats fed the combination diet showed marked reduction of DNMT1 expression and induction of histone H3 acetylation, which were accompanied by restoration of SFRP5 mRNA in normal-appearing colonic crypts. The combination diet also significantly reduced ß-catenin nuclear translocation, Cyclin D1 expression and cell proliferation. These data show, for the first time, that combination of selenium and green tea is more effective in suppressing colorectal oncogenesis than either agent alone. The preventive effect is associated with regulation of genetic and epigenetic biomarkers implicated in colonic carcinogenesis.

Selenium (Se), an essential trace element, has also been identified as an anticarcinogenic agent, with supporting evidence from epidemiological studies, clinical intervention trials, preclinical intervention studies (animal cancer models) and cell culture studies. Natural organic and inorganic sources of Se as well as synthetic organoselenium compounds have been shown to be effective; safety and efficacy factors favour the organic forms. Intakes that are several fold that purported to meet nutritional requirements (adult recommend dietary allowance--55 μg Se/day) are associated with reductions in cancer risk, but are not currently met by most diets, unless Se-rich foods are included. Further clinical studies and development of tools for speciating Se in foods will enable progress to be made in determining desirable Se forms and foods with respect to providing safe and effective ways of reducing cancer risk.

Certain forms of dietary Se may have advantages for improving human Se status and regulating the risk for disease, such as cancers, including colorectal cancer (CRC). The present study compared the effects of a Se-enriched milk protein (dairy-Se) with a Se-rich yeast (yeast-Se) on plasma Se levels and rectal selenoprotein gene expression since we reasoned that if these genes were not regulated, there was little potential for regulating the risk for CRC in this organ. A total of twenty-three healthy volunteers with plasma Se in the lower half of the population range were supplemented with dairy-Se (150 μg/d) or yeast-Se (150 μg/d) for 6 weeks, followed by 6 weeks of washout period. Blood was sampled every 2 weeks, and rectal biopsies were obtained before and after Se supplementation and after the washout period. Plasma Se levels and glutathione peroxidase (GPx) activity, and rectal mRNA of selenoprotein P (SeP), cytosolic GPx-1 (GPx-1), gastrointestinal GPx-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were measured. Plasma Se levels increased rapidly in both Se groups (P < 0·001); plasma GPx activity was not significantly changed. Rectal SeP mRNA increased at 6 weeks compared with baseline in both Se groups (P < 0·05); only dairy-Se resulted in a sustained elevation of SeP after the washout period (P < 0·05). Rectal GPx-1 and GPx-2 mRNA were higher with dairy-Se (P < 0·05) than with yeast-Se at 6 weeks. In conclusion, three rectal selenoprotein mRNA were differentially regulated by dairy-Se and yeast-Se. Changes in rectal selenoproteins are not predicted by changes in plasma Se; dairy-Se effectively regulates the expression of several rectal selenoproteins of relevance to the risk for CRC.

Certain forms of dietary Se may have an advantage in improving Se status and reducing cancer risk. The present study compared the effects of an Se-enriched milk protein product (dairy-Se) with an Se yeast (yeast-Se) on selenoprotein activity and expression in the mouse colon. Mice were fed four diets for 4 weeks: a control milk protein diet (Se at 0.068 parts per million (ppm)), dairy-Se diets with Se at 0.5 and 1 ppm, and a yeast-Se diet with Se at 1 ppm. Cytosolic glutathione peroxidase-1 (GPx-1) activity, mRNA of selenoprotein P (SeP), GPx-1, gastrointestinal glutathione peroxidase-2 (GPx-2) and thioredoxin reductase-1 (TrxR-1) were examined in the mouse colon. Dairy-Se diets did not significantly affect GPx-1 mRNA and GPx-1 activity but produced a dose-dependent increase in SeP and GPx-2 mRNA, with a significantly higher level achieved at 1 ppm Se (P < 0.05). Yeast-Se at 1 ppm significantly increased GPx-1 mRNA and GPx-1 activity (P < 0.01) but not GPx-2 mRNA. Neither Se supplement had any effect on TrxR-1. The present study indicates that selenoprotein levels in the mouse colon are regulated differently depending on the Se supplement. As we have previously shown that dairy-Se at 1 ppm was protective against colorectal cancer (CRC) in an azoxymethane-induced CRC mouse model, this up-regulation of colonic GPx-2 and SeP with Se supplementation may be crucial to its chemopreventive action.

The chemical form and bioavailability of dietary selenium may influence its protectiveness against colorectal cancer. Selenium is readily incorporated into milk proteins by feeding cows with selenized-yeast. This study examined whether a dairy source of organic selenium (as milk proteins) is more effective than a yeast source at inhibiting oncogenesis in carcinogen-treated mice and whether it regulates the homeostatic response to carcinogen-induced DNA damage. Dietary interventions are as follows: selenium-enriched milk protein isolate (Tatura-Bio Se; 0.5 or 1 ppm selenium) or milk protein control and selenized-yeast (Sel-Plex; 1 or 4 ppm selenium) with casein or casein alone as control. After 4 weeks on diet, mice received a single azoxymethane (10 mg/kg) injection to induce mutations and were killed 6 hours later. Measures were as follows: plasma selenium, cell proliferation, and acute apoptotic response to azoxymethane (AARGC). Separate groups of mice on the same diets were given 4 weekly azoxymethane (15 mg/kg) injections to induce oncogenesis. Mice were killed 6 or 30 weeks after the last azoxymethane injection. Measures were as follows: aberrant crypt foci (ACF), cancers, and K-ras mutations. Dairy-selenium at 1 ppm significantly suppressed ACF and cancers, whereas yeast-selenium at an equivalent selenium intake had no effect. Dairy-selenium significantly increased plasma selenium levels and AARGC, and reduced cell proliferation and frequency of K-ras mutations in ACF relative to an equivalent dose of selenium from yeast. Selenium-enriched milk protein isolate is superior to selenized-yeast in terms of its bioavailability and capacity to suppress oncogenesis. Suppression may be a consequence of enhanced apoptotic deletion of azoxymethane-induced DNA lesions and the subsequent reduction in frequency of K-ras mutations.

Selenium (Se) has been shown to be protective against cancers in animal models at concentrations exceeding those considered essential for normal nutritional requirements. Organic forms of Se provided as dairy proteins were obtained from cows fed diets supplemented with yeast Se. The casein extracted from milk was found to contain approximately half the Se of the Se-enriched milk. This casein was included in a semi-purified AIN rodent diet so as to provide 1 ppm Se and 25% protein and was compared with AIN diets containing no added Se (control, 0.05 ppm), 1 ppm and 4 ppm Se as selenised yeast (Sel-Plex) Their influence on colon tumor expression was examined in rats induced with azoxymethane, the diets being introduced post-induction. The selenised casein diet at this concentration was effective in reducing colon tumor incidence (by 29%) and burden (decreased 52%, P < 0.05) relative to the control in rats 26 wk post-induction. Selenised yeast, when added at similar (1 ppm) and increased Se concentration (4 ppm), did not influence significantly colon tumor expression. However, in a second study, with Se yeast providing Se at 1 ppm, 4 ppm, and 8 ppm throughout the experiment, a significant reduction in tumors was observed with 8 ppm Se (colon tumor incidence was 15% lower and colon tumor burden was 35% lower, P < 0.05). However this was associated with a significantly lower body weight in the rats (down 10.5%, P < 0.05) indicating a possible disturbance with normal energy intake or metabolism. The form in which Se is presented in the diet may influence significantly its bioavailability and/or anticancer potential at given concentrations within a safe range. The efficacy of selenised casein and indeed other potential dietary sources deserve further investigation with regard to their ability to prevent colon tumors at concentrations considered safe in the diet.

Se and green tea have been shown in epidemiological, observational and preclinical studies to be inversely related to the risk of developing colorectal cancer (CRC). However, there are limited studies to evaluate their regulatory effects on genes/proteins that relate to CRC oncogenesis in human subjects, such as selenoproteins, WNT signalling pathway, inflammation and methylation. This study examined the effects of supplementation of Se using Brazil nuts and green tea extract (GTE) capsules, alone and in combination, on targeted biomarkers. In total, thirty-two volunteers (>50 years of age) with plasma Se≤1·36 µmol/l were randomised to one of three treatment groups: nine to Se (approximately 48 µg/d) as six Brazil nuts, eleven to four GTE capsules (800 mg (-)-epigallocatechin-3-gallate) and twelve to a combination of Brazil nuts and GTE. Blood and rectal biopsies were obtained before and after each intervention. Plasma Se levels, rectal selenoprotein P (SePP) and β-catenin mRNA increased significantly in subjects consuming Brazil nuts alone or in combination, whereas rectal DNA methyltransferase (DNMT1) and NF-κB mRNA were reduced significantly in subjects consuming GTE alone or in combination. None of the interventions significantly affected rectal acetylated histone H3 or Ki-67 expression at the protein level or plasma C-reactive protein. Effects of the combination of Brazil nuts and GTE did not differ from what would be expected from either agent alone. In conclusion, supplementation of Brazil nuts and/or GTE regulates targeted biomarkers related to CRC oncogenesis, specifically genes associated with selenoproteins (SePP), WNT signalling (β-catenin), inflammation (NF-κB) and methylation (DNMT1). Their combination does not appear to provide additional effects compared with either agent alone. [ABSTRACT FROM PUBLISHER]

Selenium is an essential trace element for mammals, and a component of at least 25 selenoproteins which incorporate the amino acid selenocysteine (Sec). These proteins include a number with oxidoreductase functions. An examination of the selenoproteins and their influence on carcinogenesis in an animal model may assist in determining their relevance in chemoprevention. Food sources offer a number of organic forms of selenium, with selenomethionine a common component, as in selenised yeasts. A selenium-rich dairy protein product has been developed (TaturaBioSe, Tatura Milk Industries, Tatura, Victoria) which could improve selenium status in populations considered marginal or deficient. It could also provide higher intakes (e.g. several fold above recommended dietary intake recommendations) of potential benefit as chemopreventive to those at greater risk of some selenium-responsive diseases, such as some sporadic colorectal cancers. Clinical studies are showing it to be a safe, palatable product for consumption in the form provided. Dairy protein selenium at 1 ppm in diet had a significant chemopreventive effect compared with control (0.05 ppm Se) in an azoxymethane model of colon cancer. Colon tumour incidence in rats was down by 29%, and tumour burden (colon tumours/rat) was halved, effects not observed when an equivalent Se concentration was provided as yeast selenium. When assessed by plasma Se concentration, this dairy protein form of selenium showed greater bioavailability (as assessed by plasma selenium) as well as efficacy in chemoprevention. Programmed cell death (apoptosis) was increased in colonic crypts and crypt height significantly diminished. The influence on early changes in carcinogenesis provides an insight into possible mechanism(s) of action. Histological and biochemical assays (e.g. monitoring oxidoreductase enzymes) could potentially provide early biomarkers with clinical relevance. [ABSTRACT FROM AUTHOR]

There is interest in pre-farm gate fortification of the diet with highly bioavailable selenium (Se) to improve public health, so the aim of the present study was to determine the bioavailabilities of Se from Se-enriched whole milk and milk replacers supplemented with exogenous Se in neonatal pigs. Milk enriched with Se (1070 μg Se/kg dry matter (DM); HSeM) was obtained from cows supplemented with selenised yeast while the control milk diet (135 μg Se/kg DM; LSeM) was made using milk powder from non-supplemented cows. Additional diets were formulated by adding selenised yeast (HSP) or selenate (HSN) to the LSeM diet to give final Se concentrations of 1070 μg Se/kg DM. Neonatal pigs were trained to drink milk and then randomly allocated to their four respective diets and slaughter times (0, 7, 14, 28 and 42 days of feeding). Plasma Se increased over the first 21 days in pigs consuming HSeM, reaching a value over three times higher than the LSeM pigs. Plasma Se concentrations plateaued at 45, 125, 122 and 170 μg/mL for LSeM, HSN, HSP and HSeM pigs, respectively ( P < 0.001). After 28 days, muscle Se plateaued at 47, 106, 237 and 486 μg/kg for LSeM, HSN, HSP and HSeM pigs, respectively ( P < 0.001). Colonic selenoprotein P gene expression was greater ( P = 0.024) in pigs fed HSeM compared with LSeM while the HSP and HSN were intermediate. These data suggest that Se in milk from cows fed selenised yeast is highly bioavailable and may offer a means of delivering supplemental Se to humans. [ABSTRACT FROM AUTHOR]