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PubMed2000

Effect of three diaryl tellurides, and an organoselenium compound in trout erythrocytes exposed to oxidative stress in vitro.

Previous literature reports have demonstrated that nucleated trout erythrocytes in conditions of oxidative stress are subjected to DNA and membrane damage, and inactivation of glutathione peroxidase. The present study was undertaken to evaluate the ability of three diaryl tellurides and the organoselenium compound ebselen to protect trout (Salmo irideus) erythrocytes against oxidative stress, induced thermally and by a variation of pH. The antioxidant ability of these molecules was evaluated through chemiluminescence. Impairment of DNA was assessed using the comet assay, a rapid and sensitive single cell gel electrophoresis technique, used to detect primary DNA damage in individual cells. At low concentrations (<10 microM), all the compounds used presented a protective effect on DNA damage without altering the hemolysis rate. In higher concentrations, they accelerated the hemolysis rate and two of the diaryl tellurides were strongly genotoxic.

Animals↗

PubMed2004

In vitro cytogenetic testing of an organoselenium compound and its sulfur analogue in cultured rat bone marrow cells.

BACKGROUND: Selenium (Se) is a non-metal element, occurring in varying degrees in the environment and it has been found to be a component of several enzymes. Different selenium compounds have been associated with carcinogenicity, toxicity, modification of metal toxicity and prevention of cancer. Organoselenium compounds had substantially greater bioavailability and less toxicity than that of inorganic selenium. From a chemical point of view, Se resembles sulfur (S) in many of its properties, thus, Se and S may be considered to be isosteric. The ability of a synthetic organoselenium compound; cyclopenta-dienyldicarbonyl ironselenoterephthalic acid (CSe) and its sulfur analogue (CS) in the range of 10-8 to 10-5 M, to induce sister-chormatid exchanges (SCE) and alter cell division expressed as mitotic index (MI) as well as cell survival has been investigated. METHODS: Rat bone marrow cells were cultured in the presence of CSe and CS in the range of 10-8 to 10-5 M with a total exposure time of 4, 16 or 28 h at 37 degrees C. Fluorescence-plus-Giemsa (FPG) technique was used to visualize chromosomes for SCE analysis and MI determination. Trypan blue exclusion technique was used to determine cell viability. RESULTS: At the three exposure times, cell survival progressively decreased with increasing concentration, but the effect of either chemical was not significant (ANOVA; P < 0.05) as compared to the negative control. Significant reductions in MI were calculated at the highest concentration (10-5 M) when either chemical was applied for 16 or 28 h. Furthermore, the mean SCE increased with longer exposure times and, in general, CSe had slightly greater effect on cell survival and caused higher frequencies of SCE than CS. The exception was the 10-8 M treatment. However, both CSe and CS failed to induce 2-fold SCE as that of the negative control and therefore they are not considered as mutagens. CONCLUSION: Both CSe and CS in the range of 10-8 to 10-5 M could not double the SCE rate of the negative control and therefore not considered as mutagens at these experimental conditions.

Journal Article↗

PubMed2004

Analysis of organoselenium compounds in human urine using active carbon and chemically modified silica sol-gel surface-assisted laser desorption/ionization high-resolution time-of-flight mass spectrometry.

Laser desorption/ionization time-of-flight mass spectra of three thermally labile low molecular weight organoselenium compounds (selenomethionine, selenoethionine, trimethylselenonium iodide) in human urine matrix have been obtained by using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). Four active layers, active carbon, silica sol-gel, and silica sol-gel impregnated with crown ether and with active carbon, were deposited on three different support substrates: (i) microscope slide coverslips; (ii) Al foil; and (iii) Cu tapes. Primarily protonated molecular ions and alkali metal adducts were observed in the mass spectra. A mixed-silica sol-gel and active carbon substrate active layer gave the best signal response for all compounds. Sol-gel substrates offered very clean backgrounds compared to the pure active carbon layers; however, the mass spectral signal intensities acquired were substantially lower for the sol-gel surfaces than those of the pure active carbon under the same conditions. Cu tape and Al foil support materials gave strong mass spectra of molecular ions and alkali metal molecular ion adducts, with lower Na and K adducts found with the Cu tape than with Al foil. Glass coverslips gave no response under all experimental conditions examined. Aerosol deposition was used to prepare SALDI substrates to avoid the localized "sweet spot" phenomenon encountered in conventional SALDI substrate preparation. Various nebulizers were examined and found to be effective in producing SALDI films with controlled and reproducible thicknesses. We were able to obtain exact mass identification of all three selenium species by high-resolution TOF-MS. To the best of our knowledge, this is the first time low molecular weight organoselenium compounds have been identified by SALDI-high-resolution TOF-MS.

Carbon↗

PubMed1994

Inhibition of thymidine kinase in cultured mammary tumor cells by the chemopreventive organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.

To identify mechanisms by which the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) mediates its chemopreventive activities, we have examined its effects on cell lines derived from breast cancer of humans and rats. When log-phase cells were treated with a dose of 1 microM p-XSC, we observed a significant decrease in thymidine kinase (TK) activity within 4 h, and reduced thymidine incorporation after 24-48 h. When the dose of p-XSC was increased to 2 microM, the decrease in TK was accompanied by a modest, but significant, decrease in thymidine incorporation at 4 h, and a greater inhibition after 24-48 h. At a dose of > or = 3 microM, we observed a large decrease in TK, accompanied by > 70% reduction in thymidine incorporation, as well as decreases in mitochondrial activity and cell numbers, all within 4 h. Equal concentrations of selenium in the form of Na2SeO3 had no effect on the parameters described above. These data suggest that inhibition of thymidine kinase is an early effect of p-XSC in cultured breast tumor cells.

Adenosine Triphosphate↗

PubMed2000

Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung carcinogens present in tobacco smoke. A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 micromol/mouse) and NNK (3 micromol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks. Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after carcinogen administration. Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model. Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver. Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver. Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPX(Se)), GST-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver. These studies suggest that the chemopreventive efficacy of p-XSC, when fed during carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these carcinogens, and the induction of specific phase II enzymes involved in their detoxification. The mechanisms that account for the effect of p-XSC when fed after carcinogen administration remain to be determined.

Animals↗

PubMed2004

Organoselenium compounds as potential therapeutic and chemopreventive agents: a review.

Selenium is an essential trace element. It is, however toxic at concentration little above which is required for health. Selenium is incorporated into proteins as selenocysteine, the 21(st) amino acid. Selenoproteins are found in bacteria, archaea and eukaryotes. Biochemical and physicochemical properties of selenium result in the unique redox characteristics of selenocysteine and its use in antioxidant enzymes. In this context of a redox reaction is the reduction of reactive oxygen metabolites by glutathione peroxidases, helping to maintain membrane integrity, reduces the oxidative damage to lipids, lipoproteins, and DNA. Selenium has structural and enzymatic roles. Selenium influences a number of endocrine processes, most notably, those involved in thyroid hormone synthesis and metabolism. Se is needed for the proper functioning of the immune system, a role in viral suppression, AIDS, and also is implicated in delaying the aging process. Its deficiency has been linked to a number of disorders such as heart disease, diabetes, and diseases of the liver, and it is required for sperm motility and may reduce the risk of miscarriage. Se supplementation has recently moved from the realm of correcting nutritional deficiencies to one of pharmacological intervention, especially in the clinical domain of cancer chemoprevention. During the last few years, a tremendous effort has been directed toward the synthesis of stable organoselenium compounds that could be used as antioxidants, enzyme modulators, antitumor, antimicrobials, antihypertensive agents, antivirals and cytokine inducers. The biochemistry and pharmacology of selenium-based compounds are subjects of intense current interest, especially from the point of view of public heath. The purpose of this review is to discuss the recent pharmacological applications of organoselenium compounds as therapeutic agents in the treatment of several diseases.

Animals↗

PubMed1997

Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets.

BACKGROUND: Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued. PURPOSE: Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets. METHODS: Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically. RESULTS: No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet. CONCLUSIONS: In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.

Adenocarcinoma↗

PubMed2006

Effects of supplementing broiler breeder diets with organoselenium compounds and polyunsaturated fatty acids on hatchability.

The effects of supplementing broiler breeder diets with polyunsaturated fatty acids (PUFA) and organoselenium compounds on fertility, hatchability, and the weight of 1-d-old chicks was assessed. Prepeak (23 wk) and peak (27 wk) production breeders were fed 1 of 4 diets: a wheat-based commercial breeder diet with 55 g/kg of either soybean oil (SO) or fish oil (FO), but no added Se (only that originating from feed ingredients), and each diet with added Se as Sel-Plex (SO + Se, FO + Se). The diets were designed to contain <0.1 mg/kg of Se and about 0.5 mg/kg of Se for the nonsupplemented (no added Se) and the supplemented diets, respectively. The Se concentration of the eggshell of the hatching egg was measured. The concentration of Se, PUFA, and total lipid content of the brain and liver of the 1-d-old chick was determined. The number of fertile eggs increased, embryonic mortality decreased, and hatchability increased as hen age increased from 23 to 27 wk. The Se concentration in the eggshell and the brain and liver of 1-d-old chicks was higher in the high-Se treatments com pared with the concentration in the low-Se treatments. Fish oil inclusion in the breeder diet increased embryonic mortality in wk 3 of incubation and reduced both hatchability and 1-d-old chick weight in hens of both ages. The addition of Se to the FO diets ameliorated some of these adverse effects, because chicks hatched from eggs laid by 23-wk-old breeders of the FO + Se treatment were heavier than those receiving the FO treatment. The Se concentration in the brain and liver of chicks from the FO hens was higher than that in chicks from the SO hens. The concentration of docosahexaenoic fatty acid was higher in the liver of chicks from the SO + Se treatment compared with that of chicks from the SO treatment, indicating possible protective effects of Se. Hatchability was decreased by increased PUFA and was higher in 27-wk-old compared with 23-wk-old breeders.

Animal Feed↗

PubMedDate not supplied

Evaluation of organoselenium compounds for potential chemopreventive properties in colon carcinogenesis.

As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium, we have evaluated benzyl selenocyanate (BSC) and its o-, m-, p-nitro and -methoxy isomers, o-, m-, and p-isomers of phenylenebis(methylene)selenocyanate (XSC), dibenzyl diselenide (DDS), and 2,2'-diselenobis[((N,N-dimethylamino)methyl)- benzene]bis(hydrochloride salt) (DSBDB) for their potential colon tumor inhibitory properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), a preneoplastic lesion, in male F344 rats prior to preclinical efficacy study. In the first experiment, the effect of these agents administered during initiation and postinitiation periods of carcinogenesis was investigated. Male F344 rats were fed diets containing 8 ppm Na2SeO3 or 10 ppm of each BSC and its analogues, DDS and DSBDB or 20 ppm of each XSC analogue, two weeks prior to AOM (15 mg/kg body wt., once weekly for two weeks, s.c.) administration and during and until 8 weeks after AOM treatment. Formalin-fixed and methylene blue stained colons were scored for AOM-induced ACF using the light microscope. Taking body weight gains and multiplicity of 4 or more AC/focus, the inhibitory effects of Na2SeO3, o-, m- and p-methoxy-BSC, p-XSC and DDS were much greater than those of the other selenium compounds. In the second study, the effects of these agents when administered during the initiation or postinitiation periods were investigated. The results indicated that o-, m-, and p-methoxy-BSC, DDS and p-XSC significantly inhibited crypt multiplicity during the initiation period whereas o-, and p-methoxy-BSC, p-XSC and DDS suppressed crypt multiplicity during the postinitiation period. It is concluded that o-, and p-methoxy-BSC, p-XSC and DDS possess potential chemopreventive properties in colon cancer. Further studies are warranted to evaluated these agents for chemopreventive properties in preclinical efficacy studies.

Animals↗

PubMed2000

Liquid chromatography/electrospray mass spectrometry of organoselenium compounds with postcolumn crown ether complexation.

Postcolumn addition is an effective means of alleviating or solving ionization-related problems in liquid chromatography/electrospray ionization mass spectrometry (LC/ESIMS). In the current study, initial attempts to develop a direct LC/ESIMS method for an organoselenium compound, 4-hydroxyphenyl 2-methyl-2-aminoethyl selenide (HOMePAESe), were unsuccessful because of extensive fragmentation which occurred even under the mildest in-source collision-induced dissociation (CID) conditions. To reduce the extent of compound fragmentation, a crown ether, 18-crown-6, was added postcolumn to the system, forming a complex with HOMePAESe, which survived the electrospray ionization process with reduced fragmentation and hence improved sensitivity for the major ions. The general applicability of this crown ether complexation approach to clinical samples was demonstrated by the analysis of HOMePAESe in human urine, using a structural analogue, 4-fluorophenyl 2-aminoethyl selenide (FPAESe) as an internal standard. The limit of detection for HOMePAESe, based on a signal-to-noise ratio of 3:1, was estimated to be 5 pg/microL in urine. The potential application of this approach to the general analysis of other amine-containing compounds was also evaluated.

Chromatography, Liquid↗

PubMed2003

[Induction of apoptosis in prostate cancer cell line PC-3 by BBSKE, a novel organoselenium compound, and its effect in vivo].

OBJECTIVE: To investigate the effects of BBSKE (1,2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)]ethane), a novel organoselenium compound, on the proliferation and apoptosis of the prostate cancer cell line PC-3, and to study its effect on the growth of prostate cancer in vivo. METHODS: Prostate cancer cells of the cell line PC-3 was cultivated in media with different concentrations of BBSKE and cisplatin. The inhibition of proliferation was measured by colorimetric MTT assay. The morphologic changes were observed by fluorescence microscopy, DNA fragmentation was visualized by agarose gel electrophoresis, and the DNA degradation was determined by flow cytometry. Western blot analysis was used to identify the expression of bcl-2 and bax. The activity of caspase-3 was determined by a micro-ELISA reader. Mouse prostate cancer cells of the TRAMP-C2 line were cultured and then injected subcutaneously into 2 male C57BL/6 mice to establish the animal model. Then the 2 mice were killed to collect the cancer cells. Twenty-four mice were injected intraperitoneally with single cell suspension of TRAMP-C2 cell and then divided into 3 groups of 8 mice undergoing intraperitoneal injection for 7 days: BBSKE group (BBSKE was administered at the dosage of 25mg/kg/day), cisplatin group (cisplatin 2mg/kg/d was injected), and control group (pure solvent was injected). Three weeks after the mice were killed and the tumors were taken out to calculate the inhibition rate. RESULTS: BBSKE inhibited the growth of the PC-3 cells dosage-dependently with a value of IC(50) of 17.90 micro mol/L after a 48 h exposure, higher than that in the case of cisplatin (15.00 micro mol/L). After exposure of PC-3 cells to BBSKE at the dosage of 20 micro mol/L for 48 hours the apoptosis rate was 26.32%, significantly higher than that of the control group (1.75%, P < 0.01). The expression of bcl-2 was decreased and the expression of bax remained almost unchanged along with the increase of BBSKE concentration. The activity of caspase 3 in the subgroup of BBSKE of the concentration of 5 micro mol/L remained almost unchanged, and was increased to 3.65 +/- 0.57 and 4.39 +/- 1.01 respectively in the BBSKE 10 micro mol/L and 20 micro mol/L subgroups, both significantly higher than that of the control group (both P < 0.05). In the in vivo experiment, the growth of tumor was significantly inhibited by BBSKE with an inhibition rate of 40% and the inhibition rate of the cisplatin group was 48%. CONCLUSION: The novel organoselenium BBSKE inhibits the proliferation of PC-3 cell and promote its apoptosis, probably through downregulating the expression of bcl-2 and the activity of caspase-3. BBSKE also inhibits the growth of prostate cancer in vivo.

Animals↗

PubMed2001

Mechanisms of organoselenium compounds in chemoprevention: effects on transcription factor-DNA binding.

Data obtained on the effects of selenium compounds on regulatory transcription factor-DNA binding by other laboratories are briefly reviewed, and some of our own results in this area are also presented. We assessed the in vitro and in vivo effects of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on the binding activities of the transcription factors nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), Sp1, and Sp3 using the HCT-116 (human colorectal adenocarcinoma) cell line as a model system. Using nuclear extracts, electrophoretic mobility shift assays were carried out to determine the extent of binding of the transcription factors to their respective consensus recognition sites on radiolabeled oligonucleotides. p-XSC and sodium selenite reduced the consensus site binding activity of NF-kappa B in a concentration-dependent manner when nuclear extracts from cells stimulated with tumor necrosis factor-alpha were incubated with either compound ("in vitro"). However, only p-XSC inhibited NF-kappa B consensus recognition site binding when the cells were pretreated with either compound and were then stimulated with tumor necrosis factor-alpha ("in vivo"). In contrast, the consensus site binding activity of AP-1 was inhibited only with sodium selenite, but not with p-XSC in vitro or in vivo. p-XSC or sodium selenite reduced the consensus site binding of transcription factors Sp1 and Sp3 in concentration- and time-dependent manners when nuclear extracts from cells treated with either compound in vivo were assayed by electrophoretic mobility shift assay. 1,4-Phenylenebis(methylene)thiocyanate, the sulfur analog of p-XSC, which is inactive in chemoprevention, had no effect on the oligonucleotide binding of Sp1 and Sp3. Our observations could provide further clues as to the mechanisms involved in the chemoprevention of cancer by p-XSC.

Animals↗

PubMed1995

Chemoprevention of cancer by organoselenium compounds.

A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short-term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long-term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4-phenylenebis(methylene)selenocyanate (p-XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p-XSC inhibited mammary tumor development induced by 7,12-dimethylbenz(a)anthracene (DMBA) during both the initiation and post-initiation phases of carcinogenesis in female CD rats. p-XSC inhibited DMBA-DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p-XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p-XSC was also shown to inhibit cell growth and induce a dose-dependent increase in cell death by apoptosis. In these assays p-XSC appears superior to selenite and to its sulfur analog, 1,4-phenylenebis(methylene)thiocyanate. Dietary p-XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines.

Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous intracellular oxidoreductase system with antioxidant and redox regulatory roles. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In some human tumors, the thioredoxin system is found over-expressed. Because of its role in stimulating cancer cell growth and as an inhibitor of apoptosis, the Trx system offers a target for the development of drugs to treat and prevent cancer. In a previous research, we successfully synthesized a novel organoselenium compound BBSKE(1,2-[bis(1,2-Benzisoselenazolone-3(2H)-ketone)]ethane, BBSKE, PCT: CN02/00412) targeting the TrxR, and it has demonstrated the inhibitory effect on the growth of a variety of human cancer cells from various organs. In this study, we investigated the inhibitory effect of BBSKE on TrxR activity in PC-3 and DU145 human prostate cancer cell lines, and its antitumoral effect on these two cell lines. Treatment of BBSKE inhibited the TrxR activity in both of the cell lines in a dose-dependent manner and it also inhibited the proliferation of these two cell lines in a dose-dependent manner. Cell cycle analysis showed S phase arrest in both of the cell lines following 48 h exposure to BBSKE. During the S arrest, analysis of cell cycle regulatory proteins demonstrated that BBSKE increased the protein levels of cyclinA, cyclinE, and P21, but decreased the levels of cyclinB1, cyclinD1, and Cdk4. Furthermore, BBSKE decreased the protein level of Bcl-2 but increased the level of Bax, and induced apoptosis in PC-3 and DU145 human prostate cancer cell lines. These results suggest that this novel TrxR inhibitor inhibits the proliferation of prostate cancer cells via S phase arrest and apoptosis in association with the regulation of multiple molecules in the cell cycle.

Antineoplastic Agents↗

PubMed2002

Cyclooxygenase-2 expression influences the growth of human large and small cell lung carcinoma lines in athymic mice: impact of an organoselenium compound on growth regulation.

Increased expression of cyclooxygenase-2 (COX-2) significantly enhances carcinogenesis and inflammatory reactions. Regulation of COX-2 overexpression may be a reasonable target for cancer chemoprevention. We have tested the hypothesis that levels of COX-2 expression determine the growth of human lung cancer cells in nude mice. Two cell lines, NCI-H460 (non-small cell lung cancer) and NCI-H69 (small cell lung cancer) were selected because the former expresses high levels of COX-2 protein and the latter has no detectable levels. We also examined the effects of 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a highly effective chemopreventive organoselenium compound and known inhibitor of COX-2 expression, in vivo, on cell growth and COX-2 expression in vitro in the NCI-H460 cancer cell line. Cells were exposed to p-XSC at levels between 10 and 100 microM for six days and showed toxicity at approximately 50 microM. Pre-exposure of NCI-H460 to non-toxic levels of p-XSC suppressed COX-2 protein expression in a dose-dependent manner. At 40 microM, p-XSC suppressed phorbol myristate acetate (PMA)-induced COX-2 expression in NCI-H460 cells by more than 66%. In vivo studies in athymic mice showed a significant difference in tumor volume between cell lines. Pre-treatment of NCI-H460 cells with a non-toxic dose of p-XSC, prior to their injection into nude mice, significantly suppressed tumor growth when compared to untreated cells. Collectively, the outcome of our in vitro and in vivo studies supports the hypothesis that levels of COX-2 expression determine the extent of human lung tumor growth in athymic mice. Therefore, inhibition of COX-2 expression by agents such as p-XSC provides a strong rationale for the development of future clinical prevention trials.

Animals↗

PubMed2004

Separation of organoselenium compounds and their electrochemical detection.

A simplified procedure based on ion-exchange separation of selenourea (Se-U) and selenocystamine (Se-CM), which have very close half-wave potential when they are simultaneously analyzed by voltammetric techniques, has been developed and optimized. Thus, selenocystamine remains in the cation exchanger Purolite C 100 H, whereas selenourea is found in the effluent and is determined by square wave cathodic stripping voltammetry using Na(2)CO(3 )as electrolyte. Selenocystamine is then eluted from the cation exchanger using 4 M HCl and analyzed by square wave cathodic stripping voltammetry in the HCl solution. For each voltammetric determination the corresponding parameters were investigated and optimized; the obtained detection limits were 0.3 ng Se mL(-1) for Se-CM and 2 ng Se mL(-1) for Se-U. A flow sheet for the separation of inorganic (Se(IV) and Se(VI)) and organoselenium compounds (Se-U, Se-CM, (CH(3))(2)Se(2), and (CH(3))(2)Se) developed for their electrochemical detection is presented and it was successfully applied to a certified reference material, an environmental soil sample, and a urine sample.

Adult↗

PubMed2003

Elucidation of molecular targets of mammary cancer chemoprevention in the rat by organoselenium compounds using cDNA microarray.

We employed cDNA microarray analysis to identify, in mammary adenocarcinomas induced by 7,12-dimethylbenz[a] anthracene (DMBA) in the rat, target genes as potential biomarkers for cancer chemoprevention by 1,4-phenylenebis(methylene)selenocyanate (p-XSC). Confirmation of selected genes was conducted by reverse transcription polymerase chain reactions (RT-PCR). The glutathione conjugate, p-XSeSG, a putative metabolite of p-XSC was also employed to test our hypothesis that p-XSeSG is a more effective cancer chemopreventive agent in the mammary cancer model than p-XSC. Mammary adenocarcinomas were induced by a single oral administration of 5 mg DMBA in 0.2 ml olive oil per rat at 50-55 days of age. Consistent with our previous reports, dietary p-XSC at a non-toxic dose (10 p.p.m. as selenium) significantly inhibited adenocarcinoma development, independent of feeding duration. Moreover, p-XSeSG appears to be just as effective as p-XSC when fed after DMBA administration, but was significantly less effective than p-XSC in inhibiting the induction of mammary adenocarcinomas when it was fed before DMBA and continued until termination. To delineate the molecular basis for cancer chemoprevention by organoselenium compounds, we focused our analysis on differential expression of genes known to be involved in DMBA metabolism, as well as those related to cell cycle, cell proliferation and apoptosis. p-XSC and p-XSeSG were significantly and equally effective in inhibiting levels of expression of genes associated with cytochrome P450 isoforms, but the former was more active than the latter in up-regulating the expression of those related to certain phase II enzymes. p-XSC and p-XSeSG were significantly more effective in the up-regulation of pro-apoptotic genes, such as p21CIP1/WAF1, p27KIP1, APO-1 and Caspase-3, while down-regulating cell growth regulatory genes, such as c-myc, cyclin D1, cyclin D2 and proliferating cell nuclear antigen (PCNA). To our knowledge, this is the first report that provides insights into the effects of p-XSC and p-XSeSG at the molecular level that may account for mammary cancer chemoprevention in vivo in the rat.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

Identification of volatile selenium compounds produced in the hydride generation system from organoselenium compounds.

We report a novel aqueous derivatization of selenomethionine (Semet), selenoethionine (Seet) and trimethylselenonium ion (TmSe) by NaBH4 and HCI to volatile selenium species, namely, diethyldiselenide (DeDSe), dimethyldiselenide (DMDSe), dimethylselenide (DmSe) and ethylhydrogenselenide (ESeH), in the hydride generation (HG) system. The volatile selenium compounds produced in the HG system were on-line trapped and concentrated in a U-tube that was immersed in the liquid nitrogen trap. The trapped volatile Se compounds were volatilized at 80 degrees C in a water bath, and 50-500 microL of volatile gas was injected into the GC/AED and GC/MS, respectively. It has been established that DmSe, DmDSe, and DeDSe are the predominant Se compounds that are produced in the HG system from TmSe, Semet, and Seet, respectively, followed by ESeH from Seet. Analytical methods previously employed have stated that these compounds are inactive in the HG system. Prior decomposition of Semet, Seet, and TmSe to selenous acid is essential before HG. To the best of our knowledge, current findings for the production and identification of volatile selenium compounds in the HG system are new and different from existing reports; hence, direct estimation of Semet, Seet, and TmSe is possible when coupling with a HG system using a suitable Se-specific detector.

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