Mechanisms Of Cancer Reduction By Selenium

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A number of reviews have been written on the chemopreventive effects of selenium including most recently those by Combs and Gray,71 Ganther,86 Ip,57 Schrau-zer,49 El-Bayoumy,87 and Fleming et al.88 An entire volume of Nutrition and Cancer was devoted to selenium and cancer in honor of the late Larry Clark.89 The mechanism for selenium as an anticarcinogenic element is not known but several speculations have been advanced. It is well established that the most effective dose of selenium for cancer protection is at elevated levels, often called supranutritional or pharmacological levels. The suggested mechanisms for cancer prevention by selenium include its effects on programmed cell death, effects on DNA repair, its role in selenoenzymes, its effects on carcinogen metabolism, its effects on the immune system, selenium as an antiangiogenic agent, and its specific inhibition of tumor cell growth by certain selenium metabolites. Detailed discussions have been devoted to the role of selenium in selenoenzymes, effects on carcinogen metabolism, effects on the immune system, specific inhibition of tumor cell growth and apoptosis,71 and thus these are discussed only briefly here.

10.8.1 Role of Selenoenzymes

Because GPXs act to convert peroxides to less harmful compounds and because peroxidative damage is associated with cancer, it was reasonable to assume that these peroxidases would be involved in the reduction of tumors. However, there is little information to support this possibility. The greatest protection of selenium against tumors is at high intakes, but the activities of GPXs reach a plateau at nutritional levels with no further increase at higher levels in most tissues.

Interestingly, protection by selenium as selenite against skin tumors induced in rats either by ultraviolet-B (UV-B) light90 or phorbol esters91 correlated with the activity of GPX in skin. The hypothesis was advanced that thioredoxin reductase may be involved in reduction of tumors,86 but experimental data did not support this possibility.92 Thioredoxin reductase activity was not affected by high dietary levels of SeMCYS or methylseleninic acid, precursors of methylselenol, in rat liver.

The findings that antitumorigenic amounts of selenium (1.5 mg/kg or above) reduced tissue lipid peroxidation potential only slightly93 or not at all94 suggest that those effects are independent of the function of the GPXs. Therefore, at present it is probable that antitumorigenic effects of high levels of selenium involve mechanisms unrelated to the activities of GPXs. The 15 kDa (sep 15) selenoprotein has been suggested to be involved in the reduction of tumors. The sep 15 selenoprotein is localized on chromosome 1p31, a genetic locus commonly mutated or deleted in human cancers.95 96 The sep 15 selenoprotein genes are manifested at highest levels in prostate, liver, kidney, testis, and brain in humans and mice; these levels of this selenoprotein are reduced substantially in malignant prostate cell line and in hepatocarcinoma. Because there is loss of heterozygosity at the sep 15 locus in certain human tumor types, it was suggested that this selenoprotein may be involved in cancer development, risk, or both.95 It is interesting to note that a 15-kDa protein was found in the prostatic epithelium where it accounted for about two thirds of the protein-bound 75Se.97 Unless the levels of sep 15 can be shown to be elevated with high intakes of selenium, the likelihood of its significant involvement in tumor reduction does not appear likely. However, it could still be involved in tumor reduction with nutritional intakes of selenium because the tumor suppressor gene and p53 were altered in mice where the selenocysteine (Sec) tRNA [Ser Sec] gene was deleted in transgenic mice carrying the Cre recombinase gene. This recombinase gene is under control of the mouse tumor virus, suggesting greater susceptibility of these mice to cancer.98

10.8.2 Effects on Carcinogen Metabolism

Studies of carcinogen metabolism have yielded varying results. One study yielded comparable dietary levels of selenium to reduce the formation of covalent DNA adducts of aflatoxin in the chick99 but to increase that process in the rat.100 In rats, treatment with selenium increased the hydroxylation and subsequent oxidation of azoxymethane101 and reduced DMBA-DNA adduct formation,102 thus reducing the effect of these carcinogens. Selenium supplementation of rats was shown to reduce the hepatic microsomal production of mutagenic metabolites of several carcinogens, including A,A-dimethylaniline,103 DMBA,104 2-acetylami-nofluorene,105 and benzo(a)pyrene.106 These publications indicate that while the effect may not be universal with respect of either carcinogen or host species, high-level selenium supplementation can affect carcinogen metabolism by methods that would be expected to inhibit the initiation stage of carcinogenesis.

10.8.3 Effects on Immunity

Since the immunity of patients with cancer is reduced and selenium has been shown to boost the immune system, it is logical to conclude that selenium could reduce tumors by this method. Several studies found that supranutritional levels of selenium will stimulate the cytotoxic activities of natural killer cells107-109 and lymphokine-activated killer cells.110 Two intervention human studies with the same level of selenium intake (200 |j.g/day) were shown to reduce cancer risks and improved the immunity.111,112 The enhancement by selenium of the expression of the high-affinity interleukin-2 receptor resulted in an increased capacity to produce cytotoxic lymphocytes and macrophages that can destroy tumor cells.109 Upregulation of the receptor is expected to enhance the clonal expansion of cytotoxic effector cells and thereby modulating T-cell-mediated responses in response to signals generated by interleukin-2. Other roles of selenium in the immune system are suggested by recent findings that the mRNAs of several T-cell-associated genes have open reading frames resembling that of selenoprotein P and potential stem-loop RNA structures with consensus SeCys-insertion sequences,53 suggesting the possibility that they may encode functional seleno-proteins yet to be identified. Along this line, because plasma selenium levels, glutathione concentrations, and GPX activity are subnormal in HIV-infected individuals,113 selenium studies were conducted to investigate any relationships. By using 75Se-labeled human Jurkat T cells it was shown that the levels of four 75Se containing proteins (57, 26, 21, and 15 kDa species) are lower in HIV-infected cell populations than in uninfected cells.114 SDS/PAGE gels indicated that these selenium containing proteins are subunits of thioredoxin reductase, cellular GPX, phospholipid hydroperoxide GPX, and the 15-kDa selenoprotein. There appeared to be greater levels of low-molecular-mass 75Se compounds in HIV-infected cells than in normal ones. While these results are intriguing, further research is needed on the relationships of selenoproteins to HIV.

10.8.4 Antitumorigenic Selenium Metabolites

It is possible that selenium can lead to the formation of selenotrisulfides involving protein sulfhydryl groups that could inhibit sulfhydryl-sensitive enzymes to impair tumor cell metabolism. Selenium was shown to inhibit bovine pancreatic ribonuclease by forming an intramolecular selenotrisulfide bridge in place of the normal one,115 and the formation of selenotrisulfides involving the sulfhydryl groups of chick hepatic fatty acid synthase resulted in inhibition of that enzyme activity.116 The selenotrisulfide produced by the thiol-dependent reaction of selen-ite, GSSeSG, can be active in inhibiting protein synthesis and enhancing apop-tosis.117118 It should be pointed out, however, that these selenotrisulfides are rather short lived and somewhat unstable, raising some questions of their long-term effects.

As noted elsewhere, the antitumorigenic effects of selenium are mediated by the methylated metabolite, methylselenol. Arsenic, which inhibits the methylation of selenide, greatly reduced the antitumorigenic effects of selenite while it enhanced the efficacy of several synthetic selenium compounds that are metabolized to methylselenol.119120 Several synthetic alkyl and aryl selenocyanates have been evaluated in animal models. The more effective of these are benzylseleno-cyanate (BSC) and 1,4-phenylene-bis(methylene) selenocyanate (p-XSC).121122 In comparisons with other selenium compounds p-XSC was shown to be more effective against tumorigenesis, but less effective as a source of selenium in supporting the expression of GPX and relatively less toxic.123 This further suggests that GPXs do not play a significant role in counteraction of tumors. Another synthetic selenium compound, triphenylselenonium chloride (TPSC), has also been found to be antitumorigenic124 but had only minimum effects in the induction GPX activity. In mice, TPSC has the greatest safety margin yet observed for any chemopreventive selenocompounds. The chemopreventive effects of such synthetic selenocompounds as BCS, p-XSC, and TPSC, which release their selenium only very slowly to the general metabolism of the element, may involve more direct effects, perhaps as effective analogs of the anticarcinogenic metabolites of natural forms of the element.71

10.8.5 Selenium and Apoptosis

The evidence indicates that one possible mechanism by which selenium reduces tumors is through its effects on apoptosis.125127 Methylselenenic acid produced a more robust response at one tenth the concentration of SeMCYS in the inhibition of cell proliferation and the induction of apoptosis in mouse mammary epithelial cells.78 Work with mouse mammary epithelial tumor cells indicates that SeMCYS mediates apoptosis by activating one or more caspases.128 Of the caspases, caspase-3 activity appeared to be activated to the greatest extent. Apparently these cells have ample lyases to convert SeMCYS to methylselenol.

There are some other factors that should be considered concerning selenium and apoptosis. The feeding of high levels of dietary selenium as selenite to rats increased hepatic concentrations of both reduced (GSH) and oxidized (GSSG) glutathiones with a decreased GSH:GSSG ratio.129 Similar changes were seen in cultured hepatoma cells treated with high levels of selenite, and selenium treatment was found to retard cell-doubling time, increasing the duration of various phases of the cell cycle. Selenium-induced increases in GSSG may affect protein synthesis because this oxidized form is known to activate a protein kinase that inactivates through phosphorylation eukaryotic initiation factor 2.130 This has also been found to be inactivated by selenite131 or its selenotrisulfide derivative, GSSeSG.132 This selenotrisulfide was found to be more effective in inhibiting the growth of Ehrlich ascites tumors in mice than either the inorganic or amino acid forms of selenium.133 Apoptotic responses have been demonstrated for cells treated with high levels of selenite,134 GSSeSG,135 p-XSC,136 or TPSC.134

The influence of selenocompounds on transcription factor-DNA binding has been summarized.137 The influence of p-XSC on the binding activities of the transcription factors nuclear factor-KB (NF-kB), activator protein-1 (AP-1), SP-1, and SP3 were evaluated both in vitro and in vivo. p-XSC and selenite reduced the consensus site binding activity of NF-kB in a concentration-dependent manner when nuclear extracts from cells (HCT-116, a human colorectal adenocarcinoma) stimulated with tumor necrosis factor-a were incubated with either selenocom-pound. However, only p-XSC inhibited NF-kB consensus recognition site binding when the cells were pretreated with either compound and were then stimulated with tumor necrosis factor-a. In contrast, the consensus site binding activity of AP-1 was inhibited only with selenite but not with p-XSC in vitro or in vivo. p-XSC or selenite reduced the consensus site binding of transcription factors SP-1 and SP-3 in concentration- and time-dependent manners when nuclear extracts from cells treated with either compound in vivo were assayed by electrophoretic mobility shift assay. Interestingly, the sulfur analog of p-XSC, which is inactive in chemoprevention, had no effect on the oligonucleotide binding of SP-1 and SP-3. Certain genes involved in the inhibition of apoptosis also contain SP-1 binding sites in their promoter regions.138 Therefore, it is likely that SP-1 plays an important role not only in the regulation of cell growth and proliferation but also in programmed cell death. Another selenocompound, GSSG, will increase the induction and translocation of NF-kB, but decreases its binding to DNA.139 Although these findings show that very high levels of selenium can impair cellular proliferation by enhancing programmed cell death, it is not all that clear whether they can be extrapolated to living systems in which tissue selenium levels tend to be several orders of magnitude less.

The regulation of protein kinase C (PKC) by selenium may be involved in cancer prevention. PKC is a receptor for certain tumor promoters.140 Oxidant tumor promoters activate PKC by reacting with zinc-thiolates present within the regulatory domain, but in contrast some selenocompounds such as methylsele-neninic acid selectively inactivates PKC.141 Interestingly, thioredoxin reductase reverses selenium-induced inactivation of PKC. However, this effect was eliminated when the selenocysteine in thioredoxin reductase was either selectively alkylated or removed by carboxypeptidase treatment.140 Similarly, Escherichia coli thioredoxin reductase, which is not a selenoprotein, was also not effective, indicating a specific effect of the selenoenzyme. Other studies indicate that the PKC pathway is involved in induction of the selenoproteins, thioredoxin reduc-tase, and GPX,142143 further suggesting the influence of this pathway on selenoen-zymes.

The induction of apoptosis has been attributed to changes in genes such as cyclin-dependent kinase 2 (cdk2) and gadd45.125 144 The cdk2 and DNA damage-inducible gadd genes are related to cell cycle arrest. In vitro, SeMCYS has been reported to arrest mouse mammary tumor epithelial cells at a phase that coincided with a specific block of cdk2 kinase and an elevated expression of gadd34, gadd45, and gadd153.143 The alterations in cdk2 and gadd45 suggest that the effect of selenium in these cells may be related to the P53-mediated apoptosis. The P53 protein is a factor that enhances transcription of several genes, including gadd45. In work with LNCaP human prostate cancer cells, selenite treatment led to a significant increase in P53 phosphorylation on Ser-15.145 In contrast to this apoptotic sensitivity, these cells were rather resistant to similar concentrations of the methylselenol precursor, methylseleninic acid.

In general, there is a correlation between the effectiveness of selenocom-pounds as chemopreventive agents in vivo and their ability to inhibit cell growth and induce apoptosis in vitro.146 The influence of GSSeSG and p-XSC on normal human oral mucosa cells and human oral squamous carcinoma cells (SCCs) were investigated. SCCs were significantly more sensitive to induction to apoptosis by GSSeSG than normal human oral mucosa cells, but the differences were marginal with p-XSC. Both selenocompounds induced the expression of Fas ligand in oral cells to a degree that correlated with the extent of apoptosis induction. Also, both selenocompounds induced the stress pathway kinases, Jun NH2-terminal kinase and p38 kinases at concentrations causing apoptosis. In work with the LNCaP human prostate cancer cell line after acute exposure to selenite, they exhibited mitochondrial injury and cell death, mainly apoptosis.147 Upregulation by selenite of the cyclin-dependent kinase inhibitor p21 correlated with cell growth inhibitions.

10.8.6 Selenium and DNA Repair

It was shown that Semet can activate p53 by a redox mechanism independent of DNA damage.148 By using a peptide containing only p53 cysteine residues 275 and 277, the importance of these residues in the Semet-induced response was demonstrated. Mouse embryo fibroblasts wild-type or null for p53 genes were used to obtain evidence that the DNA repair branch of the p53 pathway was activated. In further work, Semet was shown to induce a DNA repair response in normal human fibroblasts in vitro and protects cells from DNA damage.149 It has been estimated that each cell sustains approximately 10,000 potentially mutagenic lesions per day due to endogenous DNA damage and the potential of selenium inducing DNA repair hold great value. Because SeMCYS has been shown to be the most effective selenocompound against mammary tumorigenesis, it will be interesting to determine if this compound is more effective than Semet in activation of the p53 tumor suppressor protein and thus DNA repair.

Work by other researchers indicated that thioredoxin reductase was induced but GPX was repressed in malignancies relative to controls in transgenic mice and prostate cell lines.113 In the colon cell line, p53 expression resulted in elevated GPX but repressed thioredoxin reductase. The data indicated that thioredoxin reductase and GPX are regulated in a contrasting manner in the cancer systems tested and reveal the p53-dependent regulation of selenoprotein expression. If selenium activates p53 as indicated above,148 then this could be a mechanism whereby selenium induces apoptosis because p53 is involved in this program cell death. Thus, further investigations into the involvement of selenium in DNA repair appear to be an extremely fruitful avenue to pursue.

10.8.7 Selenium as an Antiangiogenic Agent

Angiogenesis, which is the process of formation of new microvessels from existing vessels, is a critical and obligatory component of promotion, progression, and metastasis of solid cancers. The chemopreventive effect of increased selenium intake against chemically induced mammary carcinogenesis is associated with reduced intratumoral microvessel density and an inhibition of the expression of vascular endothelial growth factor.150 The results suggest a methylselenol specific inhibition of the angiogenic switch mechanism through multiple processes.

The evidence indicates that selenium exerts its cancer chemopreventive activity through an anti-angiogenic mechanism.151 The mammary carcinomas in rats fed diets with either selenium-enriched garlic or selenite were 24 to 34% lower than in those animals fed the control diet. The reduction of small vessels by selenium treatment indicated that mechanisms governing the genesis of new vessels were inhibited by this element. Based on data from several laboratories it was concluded that selenocompounds that feed into the hydrogen selenide pool will be less desirable as chemopreventive agents for humans and, conversely, those that enter the methylselenol pool would be more desirable selenium forms for human application.151

10.9 forms of selenium in foods and supplements

The efficacy of various selenocompounds using the mammary tumor model has been summarized in Table 10.1. The incidence of breast cancer is greatest of all cancers in women, but it is the third highest cause of all cancer deaths in the U.S.,152 probably reflecting the improved methods for detecting and treatment of breast cancer compared to other cancers. Although usually not mentioned, a small number of men develop breast cancer with even some deaths. About 400 men die of breast cancer each year compared to 43,300 breast cancer deaths in women in the U.S.

SeMCYS and selenobetaine are the most effective selenocompounds identified thus far against mammary tumorigenesis in animals (Table 10.1). Although selenobetaine is just as effective, SeMCYS is considered the most interesting selenocompound because it is the predominant one present in selenium-enriched plants such as garlic,153 broccoli florets,153 onions,154 sprouts,155 and wild leeks.156 In contrast, most of the selenium in enriched wheat grain,157 corn and rice,158 soybeans,159 and selenium-enriched yeast153 is Semet. Selenium-enriched yeast is the most common source of selenium available commercially.49 The selenoamino acid, Semet, is also available to the public. Selenobetaine has never been detected in selenium-enriched plants. Therefore, SeMCYS has received the most recent attention as possibly the most useful compound for cancer reduction. Except for Semet and selenocystine, the other selenocompounds listed in Table 10.1 are not present in plants and thus are mostly of academic interest. However, some of them are of therapeutic interest.

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