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At least 19 recordsLinked to original sources
PubMed2001

Molecular mechanisms of cancer prevention by selenium compounds.

Selenium compounds that are chemopreventive in animal models inhibit cell growth and induce apoptosis in vitro, and this could explain how they reduce the outgrowth of tumor cells in vivo. Our recent work has shown that primary cultures of oral carcinoma biopsies are significantly more sensitive than normal oral mucosa cultures to induction of apoptosis by a natural selenium metabolite [selenodiglutathione (SDG)], and this is associated with induction of Fas ligand, a well-known mediator of apoptosis in other contexts, and activation of so-called stress kinase signaling pathways, particularly the Jun NH2-terminal kinase (JNK). Heme oxygenase, another marker of stress responses, is also induced by selenite and SDG. The selective activation of the Fas pathway in carcinomas could be responsible directly for their destruction by apoptosis or target them for attack by immunologic responses. In contrast, although the potent pharmacological selenium chemopreventive agent 1,4-phenylenebis(methylene)selenocyanate (p-XSC) also induces Fas ligand, heme oxygenase, and stress kinase pathways, apoptosis/Fas induction is not so strongly JNK-dependent and p-XSC does not show tumor selectivity. These differences in mechanism between SDG and p-XSC may be due to the manner in which they induce redox changes in the cells, since although the effects of SDG and p-XSC are prevented by antioxidants such as glutathione or N-acetylcysteine, hydroxyl radical scavengers such as mannitol or pyrrolidine dithiocarbamate only protect against the effects of p-XSC.

Animals↗
PubMed1980

Induction of DNA repair by some selenium compounds.

Selenium compounds were found to induce DNA repair synthesis as a measure of DNA damage in both the isolated rat liver cell system and by Ames' Salmonella assay. In liver cells, DNA repair measured by uptake of [3H]thymidine was found to be greater with sodium selenite and selenate than with selenomethionine. In the bacterial culture system, selenomethionine inhibited the repair-deficient variant more than the selenite and selenate. These in vitro test systems have been used to indicate that selenium has a DNA-damaging potential.

Animals↗
PubMed2003

DNA damage-mediated apoptosis induced by selenium compounds.

Selenium (Se) compounds, which are the most extensively studied cancer chemopreventive agents, induce apoptotic death of tumor cells. In the current study, we show that selenite-induced apoptosis involves DNA damage. We showed that selenite-induced apoptosis as evidenced by cleavage of poly(ADP-ribose) polymerase was reduced in NIH 3T3 cells treated with ATM small interfering RNA, suggesting the involvement of the DNA damage regulator ATM. Consistent with ATM/ATR involvement, selenite was also shown to stimulate Ser-139 phosphorylation of the ATM/ATR substrate H2AX. Selenite-induced apoptosis was shown to involve DNA topoisomerase II (Top II) as selenite-induced apoptosis was reduced in Top II-deficient HL-60/MX2 cells and in HL-60 cells co-treated with the Top II catalytic inhibitor ICRF-193. Using purified human recombinant Top II, selenite was shown to induce reversible Top II cleavage complexes in vitro. In the aggregate, these results suggest that selenite-induced apoptosis, which involves ATM/ATR and Top II, is likely to be because of DNA damage.

3T3 Cells↗
PubMed2005

Possible role of glutathione in mitochondrial apoptosis of human oral squamous cell carcinoma caused by inorganic selenium compounds.

Selenium (Se) is a very effective anti-cancer agent. We studied the effects of inorganic Se compounds on induction of apoptosis by which Se compounds exert cancer chemopreventive activity. With the use of HSC-3 human oral squamous cell carcinoma cells, the present study showed that treatment with Se for 72 h, in the form of SeO2 and Na2SeO3, but not Na2SeO4, markedly induced apoptosis in a dose-dependent manner. Treatment of HSC-3 cells with 100 microM SeO2 resulted in the caspase-3-like and -9-like activation. Se compounds induced a loss of mitochondrial membrane potential (DeltaPsim), but did not induce the generation of reactive oxygen species. Treatment with SeO2 for 18 h resulted in 80% loss of reduced glutathione (GSH), which is known to be involved in the metabolism of Se. Treatment with N-acetyl-L-cysteine, or exogenous GSH, prevented the SeO2-induced apoptosis. Treatment with GSH led to the partial reverse in reduction of DeltaPsim caused by SeO2, while buthionine sulfoximine augmented the SeO2- or Na2SeO3-induced apoptosis. These results suggest that modulation of the mitochondrial redox equilibrium by Se contributes to the mitochondrial pathway, regulating caspase-9-mediated apoptosis without a concurrent increase in ROS.

Apoptosis↗
PubMed2003

Speciation of selenium compounds from high selenium broccoli is affected by the extracting solution.

The speciation of selenium compounds from high selenium broccoli (876 microg/g) depends on the extraction conditions. Twenty-seven extraction conditions were explored involving nine different buffering systems between pH 1 and pH 9. In nonbuffered extractions of broccoli, more than 40% of the spiked Se-methylselenocysteine was not recovered in the filtered solution. However, in buffered extractions, losses for Se-methylselenocysteine ranged from 10 to 20%. Mass balance indicated that approximately 30% of naturally occurring selenium in broccoli samples was volatilized and lost to the atmosphere when buffered extractions were made. Solid phase extractions indicated that the polarity of selenium compounds in solution was also dependent on the extracting solution. High-pressure liquid chromatography coupled to an inductively coupled plasma mass spectrometer was used to show that selenium compounds extracted from broccoli reacted with the extracting solution. Compound identities were assigned by matching retention times to standards of selenite, selenate, methylseleninic acid, Se-methylselenocysteine, selenomethionine, and the selenonic acids of Se-methylselenocysteine and selenomethionine. Changes in speciation were analyte-, pH-, and buffer-dependent, but generally, a higher pH resulted in more highly oxidized selenium compounds. For valid conclusions to be drawn from the analytical data, the extraction conditions should match the conditions present in the matrix or be specified for a particular application such as a simulated gastrointestinal digestion.

Brassica↗
PubMed1976

Effect of selenium compounds on selenium content, growth and 35S-cystine metabolism of skin fibroblasts from normal and cystinotic individuals.

Kidney samples from children with the inborn metabolic disease cystinosis contain 4 times more selenium (Se) than do kidney samples from normal individuals (p = 0.1). However, when cultured skin fibroblasts from cystinotic patients and normal control individuals are incubated in Se-D,L-methionine, Se-D,L-cystine, Se-cystamine X HCl, Se-urea, selenite or in medium without added selenium, only the cystinotic fibroblasts grown in Se-urea or selenite (SeO3=) contain more selenium than do the corresponding normal cells (p less than 0.05). In both types of cultured fibroblasts, the order of descending toxicity per ppm selenium is: Se-urea greater than Se-cystamine greater than Se-cystine greater than or equal to SeO3= much greater than Se-methionine. High (apparently toxic) concentrations of Se-urea and Se-cystamine lower the elevated intracellular free (nonprotein) cystine content of cystinotic fibroblasts to less than 60% of control values; at lower concentrations, these compounds raise the cystine content of these cells to over 140% of control values. Appropriate concentrations of SeO3=, Se-cystine and Se-methionine also elevate the free cystine content of the cystinotic cells. During a 75 minute incubation in 35S-cystine, the incorporation of 35S into the acid precipitable (protein) fraction of both cell types is significantly inhibited by Se-cystamine (approximately 55% control; p less than 0.05). The incorporation of 35S-cystine into glutathione is inhibited by Se-cystine (approximately 40% control) in both fibroblast types (p less than 0.05). In cystinotic cells, Se-cystamine significantly reduces incorporation of 35S-cystine into the cystine pool (40% control) as does SeO3= (67% control; p less than 0.05). Protein and glutathione synthesis in cystinotic fibroblasts are more strongly inhibited by Se-cystine and SeO3=, respectively, than in normal fibroblasts (p less than 0.05). These studies demonstrate that selenium compounds exhibit a different sequence of toxicity in fibroblasts than in the intact animal and that some previously unreported metabolic effects (i.e. inhibition of glutathione synthesis) may contribute to their toxicity.

Amino Acids↗
PubMed2002

Inhibition of ultraviolet B radiation-induced interleukin 10 expression in murine keratinocytes by selenium compounds.

BACKGROUND: Selenium is an essential trace nutrient necessary for the normal function of the immune system. Selenium compounds protect mice against ultraviolet (UV) B-induced tumours, probably by preventing oxidative damage to the host skin cells and to the host immune system. One possible mechanism of protection is that selenium can prevent oxidative stress-induced release of cytokines such as interleukin (IL)-10, which could suppress cell-mediated immunity. OBJECTIVES: To determine whether selenium compounds can inhibit UVB induction of IL-10 protein in murine keratinocytes. METHODS: The murine keratinocyte cell line PAM 212 was treated with or without selenomethionine (50-200 nmol L-1) or sodium selenite (1-50 nmol L(-1)) for 24 h before exposure to 200 J m(-2) UVB. The cells were stained with an antibody to IL-10, 24 h after irradiation. RESULTS: Preincubation with both selenium compounds inhibited UVB induction of IL-10 immunostaining, although selenomethionine was more effective. Pretreatment with 200 nmol L(-1) selenomethionine decreased IL-10 immunostaining to levels seen in the unirradiated controls. CONCLUSIONS: The protective effects of selenium against UVB-induced skin cancer in murine models may result, in part, from its ability to inhibit release of cytokines that are capable of suppressing cell-mediated immunity.

Animals↗
PubMed2000

Preliminary study on the determination of selenium compounds in some selenium-accumulating mushrooms.

Using various chromatographic techniques (size exclusion, anion exchange, and cation exchange) combined with several detectors (neutron activation analysis and atomic fluorescence spectrometry), an attempt was made to characterize selenium compounds in some edible, selenium-accumulating mushrooms (Albatrellus pes-caprae and Boletus edulis). The mushrooms contained mostly low-molecular-weight (6 kDa) selenium compounds. After proteolysis, only a small fraction of the extractable selenium could be identified as selenite (3.0-9.2%, Albatrellus pes-caprae), selenocystine (minor, Albatrellus pes-caprae; 7.5%, Boletus edulis), or selenomethionine (1.0%, Boletus edulis), leaving the form of the bulk still to be elucidated.

Agaricales↗
PubMed2006

Mechanism for proliferation inhibition by various selenium compounds and selenium-enriched broccoli extract in rat glial cells.

The objective of this study was to investigate the differential effects of various selenium (Se) compounds and Se-enriched broccoli extracts on cell proliferation and the possible mechanism responsible for the Se-induced growth inhibition. C6 rat glial cells were incubated with graded concentrations up to 1000 nM of selenite, selenate, selenomethionine (SeM), Se-methyl-selenocysteine (SeMCys), high-Se broccoli (H-SeB) extract or low-Se broccoli (L-SeB) extract for 24 and 48 h. MTT results indicated that all Se sources and levels examined inhibited C6 cell proliferation at 48 h. The results from cell cycle progression and apoptosis analysis indicated that SeM, SeMCys, H-SeB or L-SeB treatments at the concentration of 1000 nM reduced the cell population in G(0)/G(1) phase, but induced G(2)/M phase arrest and increased apoptosis and secondary necrosis in C6 cells at 24 h. The populations of apoptotic cells and secondary necrotic cells were increased by all Se sources examined. The COMET assay indicated that there was no significant DNA single-strand break found for all Se treatments in C6 cells for 48 h. In addition, the Se-induced proliferation inhibition may involve a hydrogen peroxide (H(2)O(2))-dependent mechanism with elevated cellular glutathione peroxidase (cGPX) activity. Both H-SeB and L-SeB inhibited C6 cell proliferation but H-SeB was less inhibitory than L-SeB. The proliferation inhibition by H-SeB in C6 cells is apparently related to the increased H(2)O(2) with the elevated cGPX activity, but the inhibition by L-SeB was H(2)O(2)-independent without change in cGPX activity.

Animals↗
PubMed1994

Optimization of an Escherichia coli formate dehydrogenase assay for selenium compounds.

A microbiological assay to detect different chemical compounds of selenium for potential future use in the study of the distribution of these chemical forms in foods is being developed. This assay is based on the detection, by infrared analysis, of CO2 in a culture of Escherichia coli when the bacteria are grown in the presence of various selenium compounds. The CO2 production is the result of selenium-dependent formate dehydrogenase activity, which catalyzes oxidation of formic acid produced during glucose metabolism. Smooth response curves were generated over several orders of magnitude for selenocystine, selenite, and selenomethionine. The assay detects selenium concentrations (above background) as low as 1.5 nM for selenocystine and selenite and 4 nM for selenomethionine in minimal medium. Detection of selenomethionine was enhanced (to a sensitivity of 1.5 nM) by the addition of methionine to minimal medium and was enhanced even further (to a sensitivity of 0.8 nM) by the addition of a defined mixture of amino acids. Selenomethionine could be assayed in the presence of an amino acid concentration which is proportional to the amino acid/elemental selenium ratio found in a wheat gluten reference material (NIST SRM 8418). This implies that the assay can detect selenium compounds in a variety of foods at low concentrations, avoiding the background CO2 production caused by high concentrations of non-selenium-containing amino acids. The observation that methionine enhanced selenomethionine availability for formate dehydrogenase synthesis supports studies in animals demonstrating that methionine controls selenomethionine incorporation into selenoenzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMedDate not supplied

Toxicity of selenium compounds to alveolar macrophages.

Selenium compounds released into urban atmospheres as a result of fossil fuel combustion may pose an inhalation hazard to people. Two chemical forms of selenium produced during coal combustion and present in combustion effluent are selenious acid. H2SeO3, and elemental selenium, Se. In an attempt to determine the toxicity of selenium compounds relative to other trace elements, the cytotoxicity of H2SeO3 and Se to rabbit alveolar macrophages in vitro was investigated. Macrophages were obtained by lung lavage and exposed in tissue culture after 20 h. Neither selenious acid nor elemental selenium caused cell lysis at concentrations which decreased total cell viability. Selenious acid was an order of magnitude more toxic then elemental selenium. Elemental selenium was similar in toxicity to environmental contaminants such as CdCl2 and V2O5. These in vitro cytotoxicity data can be used to predict the risk posed to people inhaling selenium compounds at levels found in urban atmospheres.

Animals↗
PubMed2006

Induction of phase II enzyme activity by various selenium compounds.

Twenty-seven selenium compounds and sixteen structurally related organosulfur compounds were tested for quinone reductase (QR) and glutathione-S-transferase (GST) inducing activity in murine hepatoma (Hepa 1c1c7) cells. Sixteen selenium compounds were able to double QR activity, and seven of them also doubled GST activity. The nine most potent compounds, dimethyl diselenide, 2,5-diphenyl- selenophene, dibenzyl diselenide, methylseleninic acid, diphenyl diselenide, benzeneseleninic acid, benzene selenol, triphenylselenonium chloride, and ebselen (2-phenyl- 1,2-benzisoselenazol-3(2H)-one), doubled QR-specific activity at levels lower than 7 microM. The concentration-dependence of QR induction and cell growth inhibition were linearly correlated (P < 0.001, r2 = 0.96) among the group of organoselenium compounds with putative selenol-generating potential, implying that both responses of Hepa 1c1c7 cells were based on these selenol metabolites.

Animals↗
PubMed2003

Antigenotoxic properties of selenium compounds on potassium dichromate and hydrogen peroxide.

Selenium is an environmental metal that occurs ubiquitously and is produced throughout the world for various industrial activities. Selenium has been reported to have anticarcinogenic and preventive effects in clinical and epidemiological studies. Selenium supplements can inhibit chemically-induced tumours. From the viewpoint of genotoxicity, selenium has not been adequately studied and an IARC review concluded that there were not sufficient data to consider it a carcinogen for man. In contrast, hexavalent chromium is classified as a known respiratory carcinogen producing DNA damage through free oxygen radicals. In the present study, a collaborative study has been carried out to evaluate the genotoxicity of selenium compounds and their possible interactions with potassium dichromate and hydrogen peroxide. Thus, in laboratory 1 (U.K.), the genotoxic effects of three selenium compounds were examined. Sodium selenate, sodium selenite, and selenous acid were investigated in the Ames test using strain TA102 and in the Comet assay using human lymphocytes, and also investigated for their interaction with potassium dichromate. In the Ames test, it was shown that potassium dichromate produced a highly mutagenic response, whilst the three selenium compounds did not. In combination, sodium selenate reduced the genotoxicity of potassium dichromate, but sodium selenite and selenous acid had no effect. In the Comet assay, potassium dichromate induced DNA damage, but so did the selenium compounds. In combination with potassium dichromate, however, only sodium selenate reduced its effect, whereas sodium selenite and selenous acid exacerbated DNA damage. In laboratory 2 (Spain), in the TK6 lymphoblastoid cell line, the Comet assay showed that sodium selenite was non-genotoxic, while potassium dichromate and hydrogen peroxide induced DNA damage. It was also shown that sodium selenite did not decrease the genotoxicity of potassium dichromate or hydrogen peroxide when administered as a pre-treatment or at the same time, or when potassium dichromate and sodium selenite treatments were for different time periods. Thus, only sodium selenate has shown antigenotoxic properties against potassium dichromate in the Ames test and in human lymphocytes in the Comet assay.

Comet Assay↗
PubMed1997

Free radical generation by selenium compounds and their prooxidant toxicity.

Selenium (Se) and many of its compounds are among the most toxic of nutrients. Selenium toxicity was first described in range animals in the western United States in the 1930's which consumed "selenium accumulator" plants of the genus Astragalus, Xylorrhiza, Oonopsis, and Stanleya. Selenites and selenates from the soil accumulate in these plants primarily as methylated selenium compounds and plants evolve dimethyldiselenide and dimethylselenide. Dietary selenium, primarily as selenomethionine and selenocysteine for humans fulfill the dietary requirement for selenoenzymes and proteins. In humans and animals excessive dietary selenium may be toxic. In vitro, selenium compounds such as selenite, selenium dioxide and diselenides react with thiols, such as glutathione, producing superoxide and other reactive oxygen species. This catalytic reaction of selenium compounds with thiols likely accounts for selenium toxicity to cells ex vivo and in vivo where the major glutathione producing organ, the liver, is also the major target organ of selenium toxicity. Selenium enzymes and selenoethers that do not readily form a selenide (RSe-) anion and compounds such as Ebselen where selenium is sequestered, are not toxic. Methylation of selenium by both plants and animals serves to detoxify selenium by generating methylselenides. Alternatively, full reduction of Se to elemental selenium (Se0) as done by some bacteria and the formation of heavy metal selenides such as Ag2Se or Hg2Se, results in a non-catalytic non-toxic form of selenium. This catalytic prooxidant attribute of some selenium compounds appears to account for its toxicity when such activity exceeds plant and animal methylation reactions and antioxidant defenses. This prooxidant activity may also account for cellular apoptosis and may provide a useful pharmaceutical application for selenium compounds as antibacterial, antiviral, antifungal and anticancer agents.

Animals↗
PubMed2004

Apoptosis is a critical cellular event in cancer chemoprevention and chemotherapy by selenium compounds.

Epidemiological studies, preclinical investigations and clinical intervention trials support the role of selenium compounds as potent cancer chemopreventive agents; the dose and the form of selenium are critical factors in cancer prevention. Induction of apoptosis and inhibition of cell proliferation are considered important cellular events that can account for the cancer preventive effects of selenium. Toxicity should always be considered a determining factor in the selection of potential chemopreventive agents. Prior to induction of apoptosis, selenium compounds alter the expression and/or activities of a number of cell cycle regulatory proteins, signaling molecules, proteases, mitochondrial associated factors, transcriptional factors, tumor suppressor genes, polyamine and glutathione levels. Depending on the form, selenium compounds can target separate pathways but more efforts are needed to learn about disrupting different pathways converging to apoptosis. Numerous selenium compounds are known to inhibit carcinogenesis in several animal models but not all of these have been examined for their efficacy to induce apoptosis or vice versa in the corresponding target organ. Studies aimed at investigating the effects of selenium compounds on apoptosis in the target organ in vivo and in vitro are limited. On the basis of information provided in this review, we recommend that additional molecular markers should be added to those proposed in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) on prostate cancer. Apart from the selenium compounds reviewed here, several novel synthetic organoselenium compounds need to be examined both in vitro and in vivo for their potential to induce apoptosis; such an investigation may provide better and mechanism-based cancer chemoprevention as well as chemotherapeutic agents.

Animals↗
PubMed1978

Interactions between selenium compounds and those of mercury or cadmium.

Two types of mechanisms are considered in this discussion of the interactions between compounds of selenium and those of cadmium or mercury: one based on a direct chemical reaction between compounds of these elements and the other based on metabolic changes induced by selenium administration and modifying the dose-effect relationship indirectly, without a reaction between selenium and the metallic compound. The second type of metabolic changes induced by selenium may explain why an increased selenium intake provides protection not only against methylmercury but also against the toxicity of methylated selenium compounds. A better understanding of the underlying mechanisms would help in assessing the importance of these interactions for man.

Animals↗