Advertisement

EPMA Journal

, Volume 1, Issue 3, pp 389–395 | Cite as

Selenium in the prevention of human cancers

  • Mikael BjörnstedtEmail author
  • Aristi P. Fernandes
Open Access
Review Article

Abstract

Selenium is an essential element with remarkable chemical properties. The similarity to sulphur results in a number of chemical interactions mainly connected to thiols and redox processes. The element modulates cell growth; in low concentrations it is absolutely required for growth and an essential component of serum free growth media. However moderate to high concentrations potently inhibit cell growth. The inhibitory effects are tumour specific and selenium induces apoptosis in malignant cells at concentrations that do not affect the viability of normal cells. Depending on concentration and chemical form selenium may prevent or treat tumour disease. Selenium supplementation has been found to be of value in preventing hepatocellular cancer by hepatitis B, in reducing the incidence of liver cancer in general and in decreasing mortality of colorectal, lung and prostate cancer. This review focuses on the current knowledge of the preventive effects of selenium with special emphasis on major human tumours. The unique chemical properties along with metabolism and preventive mechanisms are also discussed.

Keywords

General cancer prevention Carcinogenesis Redox Selenium Selenium metabolism 

Selenium—chemical properties

Selenium was discovered by Berzelius in 1818 [1]. Already in the original publication the striking similarity to sulphur and tellurium was described. However, there are a few important differences between selenium and sulphur explaining the major biological effects that are observed in biomolecules where selenium is in place of sulphur.

The atomic radius of selenium (1.79 Å) is slightly larger and the electronegativity slightly lower than that of sulphur. Both elements exist naturally in five different valence states: −2, 0, +2, +4, and +6 and all sulphur compounds have selenium analogues as exemplified in Table 1. Selenium oxides are strong oxidising agents and selenium compounds with selenium in the higher oxidation states are less stable compared to the corresponding sulphur compounds [2]. Selenols are relatively strong acids and the pKa of the selenol in selenocysteine is 5.24 compared to 8.25 for the thiol of cysteine [3]. Thus, at physiological pH the selenol of selenocysteine exists in the anionic form whereas the thiol in cysteine exists in the protonated form. This property together with the larger atomic radius and higher nucleophilicity of selenium can explain the differences in the properties of proteins containing selenocysteine compared to those with cysteine. However in selenomethionine the relatively more reactive nucleophilic selenium is blocked by a methyl group explaining why proteins containing selenomethionine have similar properties compared to methionine containing proteins.
Table 1

Sulfur compounds and selenium analogs

Sulfur compound

Selenium analog

Inorganic compounds

Hydrogen sulfide (H2S)

Hydrogen selenide (H2Se)

Sulfurous acid (H2SO3)

Selenious acid (H2SeO3)

Sulfuric acid (H2SO4)

Selenic acid (H2SeO4)

Sulfite (SO 3 2− )

Selenite (SeO 3 2− )

Sulfate (SO 4 2− )

Selenate (SeO 4 2− )

Organic compounds

Thiol (R-SH)

Selenol (R-SeH)

Thiolate (R-S)

Selenolate (R-Se)

Sulfenic acid (R-SOH)

Selenenic acid (R-SeOH)

Sulfinic acid (R-SO2H)

Seleninic acid (R-SeO2H)

Sulfonic acid (R-SO3H)

Selenonic acid (R-SeO3H)

Sulfoxide (R-SO-R)

Selenoxide (R-SeO-R)

Sulfone (R-SO2-R)

Selenone (R-SeO2-R)

Disulfide (R-S-S-R)

Diselenide (R-Se-Se-R)

The similarities together with the small differences between selenium containing biomolecules and their sulphur counterparts explain the importance of selenium for cell growth, proliferation and tumour prevention.

Selenium metabolism

The similarity to sulphur is also reflected in the metabolism of selenium. Selenomethionine and selenocysteine are indiscriminately incorporated into proteins instead of methionine and cysteine since the tRNAs cannot discriminate the selenium from the sulphur form. The presence of selenocysteine in place of cysteine may alter tertiary structures of proteins and also the activity of redox proteins if selenocysteine is incorporated at critical positions i.e. active sites or regulatory units. Selenomethionine is incorporated mainly in albumin, and thereby stored as an inactive form, with the consequent delay of metabolism [4]. Supplementation with selenomethionine will thus lead to a prolonged increase in total plasma selenium but a small or no fraction of active selenium. Eventually selenomethionine may be converted to selenocysteine by the transelenation reaction [5] or undergo cleavage of the carbon-selenium link by gamma lyase, the latter reaction however is believed to be of minor importance in mammals [6]. Selenocysteine is cleaved by beta-lyase to alanine and selenide [6].

The redox active naturally occurring selenium compound selenite (SeO 3 2− ) will efficiently react with free or protein bound thiols, at an exact stoichiometry, to form selenium trisulfides [7]:
The appearance of selenium trisulfides may cross-link proteins resulting in impaired protein function and this mechanism may explain some pharmacological/toxic effects of selenium [8]. Furthermore a number of chemical modifications of the active sites of redox proteins may markedly influence the activity and form the base for the diverse biological effects of selenium (Fig. 1).
Fig. 1

Cellular mechanisms of selenium on carcinogenesis

Selenodiglutathione (GS-Se-SG) is an extensively studied redox active selenotrisulfide. Selenite and GS-Se-SG efficiently reacts with thiols. Reactions of these compounds with GSH and glutathione reductase [9], the thioredoxin system [10, 11] and the glutaredoxin system [12] are described. In the absence of oxygen the reaction of selenite terminates after the consumption of 3 molecules of NADPH consistent with the formation of selenide (Se2−):

GS-Se-SG is also reduced to selenide anaerobically. In the presence of oxygen, selenide redox cycles with oxygen leading to a non-stoichiometric consumption of NADPH [10, 11]. Redox active selenium compounds are effectively reduced by free cysteine. This reaction may be of particular importance since a reducing environment, with high amounts of free thiols, will facilitate selenium uptake [13].

Selenomethylselenocysteine (SeMSeC) is a natural monomethylated species found in plants e.g. garlic, onions and broccoli. The molecule is inert but in the presence of beta-lyase the highly reactive monomethylselenol (CH3SeH) will appear [6, 14]. Like selenide monomethylselenol will redox cycle with oxygen [15]. Monomethylselenol may undergo methylation to dimethylselenide ((CH3)2Se) or trimethylselenonium ((CH3)3Se+) or demethylation by demythylase to selenide [6, 14].

One central role of selenium is the presence of this element in selenoproteins. There are 25 known selenoproteins [16] with diverse functions. In this group several important redox enzymes are found including the glutathione peroxidase family and thioredoxin reductases [17]. The synthesis of selenoproteins is complex and the incorporation of selenocysteine at an exact position within a selenoprotein follow a unique mechanism [18] requiring the efficient production of selenide. Physiological as well as preventive effects of selenium are not solely explained by selenoproteins but also by redox modulations and redox cycles further treated in the following sections. This means that redox active selenium compounds that are precursors to selenide and monomethylselenol e.g. selenite, GS-Se-SG and selenomethylselenocysteine are particularly relevant as supplements. In Fig. 2 the precursors, key metabolites and the relation to antitumour effects are summarised.
Fig. 2

Redox cycling of selected selenium compounds and metabolites

The fraction of selenide that is not used for selenoprotein synthesis is either metabolised to selenosugar, 1-Glutathionylseleno-N-acetyl-D-galactosamine and 1-methylseleno-N-acetyl-D-galactosamine [14, 19] or methylated to trimethylselenonium prior to excretion [20].

Preventive effects of selenium

Selenium has a long history as a cancer preventive agent. Several (more than 100) animal studies are reported supporting cancer preventive effects, but animal studies are often difficult to translate to humans why this review focuses on human trials. A few population studies addressing total cancer incidence have been published [21, 22, 23, 24] and the results are far clearer with selenium compared to other so-called antioxidant [25, 26] where many contradictory data are present. Some of these studies show a correlation between low serum selenium levels and increased incidence of mainly breast cancer [27], gastrointestinal cancers [28] and prostate cancer [29]. The major effects of supplementation have been observed in the incidences of colorectal-, lung and prostate cancers along with a drastic decrease in the total cancer mortality by 50% [21]. There is also a clear correlation to dose and the base line selenium status of the study population [30]. In the case of prostate cancer beneficial effects are clear only in populations with a low base line selenium level and a low intake [31, 32, 33].

Prevention of liver cancer has been observed in endemic areas of hepatocellular carcinoma and hepatitis in China. In the studies selenium was supplemented in the table salt where the study population were given up to 50 micrograms daily. The study population was matched to a control group and after 8 years the incidence of hepatocellular carcinoma was 35% reduced in the selenium-supplemented group [34, 35]. A further trial exclusively including patients with hepatitis B revealed a clear decrease in the incidence of hepatocellular carcinoma; seven out of 113 patients had developed HCC in the control group compared to none in the selenium group [35].

These studies show remarkable effects of selenium in the prevention of tumours and also clearly demonstrate the unique properties of selenium compared to other antioxidants. As will be discussed below selenium is far from just an antioxidant and the mechanism of prevention is complex including both antioxidant, prooxidant and redox regulatory effects. These important distinctions explain the differences between selenium and all traditional antioxidants lacking clear and consequent cancer preventive effects.

There was a great disappointment in the field of selenium-mediated cancer chemoprevention in 2009 when the SELECT-trial was closed prior to schedule due to lack of effects and non-significant increase in the incidence of prostate cancer in the vitamin E group compared to control along with a non-significant increase in the incidence of diabetes type II in the selenium group [36]. The design of this trial was different compared to previously published positive trials on three levels; first selenomethionine was used, second selenium was mixed with high doses of vitamin E, third the study population was only men with a high basal level of selenium and a high intake [37]. In previous studies selenised yeast has been used or inorganic redox active selenium. Selenised yeast is a mixture of methylated species where the main fraction is selenomethionine [38]. However even other methylated species are included as exemplified by the highly active selenomethylselenocysteine that is the precursor to monomethylselenol [20, 38]. This is an important difference that may be a contributing factor to the disappointing results. Furthermore, vitamin E in high doses might abolish redox effects by active selenium compounds whereby interfering with the action of selenium in a negative way (further discussed in the section below).

The data underline the importance to consider study population and selenium species before starting a large scale prevention study. Furthermore, in order to monitor the selenium uptake and efficacy of chemical species administered, biomarkers shold be considered. By such biomarkers, the metabolic status could be followed at an individual level, thereby avoiding false conclusions [39].

Preventive mechanisms of selenium

Selenium compounds can affect carcinogenesis at different stages of the process (Fig. 1) and vary depending on the form of selenium administered. The underlying molecular mechanism is not entirely understood even though several biochemical/biological processes have been identified [40]. Furthermore, the effects observed occurs at systemic, cellular and molecular level, including gene expression and direct protein alterations [14].

Preinitiation effects of selenium

The antioxidant role of selenium is believed to be the most important preventive effect at very early prenepolastic onset. The antioxidant effects can in turn be almost directly attributed to redox active selenoproteins, as selenium mainly exerts its antioxidant function as a constituent of selenocystein containing selenoproteins, were selenium supplementation increases their levels [41]. These proteins play a central role in upholding the redox homeostasis within the cell acting as ROS detoxifying agents, and thus reducing the intracellular environment [42]. In addition to the reduction of oxygen species they play a crucial role in reducing intra- and intermolecular disulfides or mixed disulfides/selenides.

Selenoproteins like thioredoxin reductase and glutathione peroxidase have via their role as redox regulators in the cell, affecting many biological processes, a most certain cancer preventive role [33]. However, their role has been shown to be far more complex as their cytoprotective effects in established tumours have been shown to turn them into cancer promoting agents. Apart form acting as cancer promoting agents, these proteins have also been implicated in drug resistance for several cytostatic agents [41].

Another important property of selenium in cancer prevention is its chemical ability to interact with metals, as several metals have been reported to increase the risk of cancers [43]. Selenium has been described to interact with metals like Au, Pt, Cd, Co and Hg etc [43, 44]. Cadmium is for instance one key element for developing prostate and breast cancer and selenium have been reported to protect against cadmium induced peroxidative damage [45]. Several of these metals can react and inhibit essential proteins like thioredoxin reductase, and may thus exert their toxic effect by modulating the redox balance in the cell. Selenium in this case acts as a detoxifying agent by chelating the metal. In a reverse manner metals like copper have a protective effect against dietary selenium toxicity [46].

Several genomic approaches have been used to elucidate the cancer preventing effects of selenium. It is evident from these studies that selenium can counteract tumour progression by reversing the expression of genes implicated in carcinogenesis [47]. Several genes have been identified including upregulation of genes related to phase II detoxifying enzymes [48], tumour suppressor genes, selected apoptotic genes including certain caspases. In addition selenium has been shown to alter the expression of genes associated to cell cycle regulation in a manner that is consistent with growth inhibition [49]. Proteomic studies have also been performed after selenium supplementation showing clear differences in the abundance of some proteins [50].

Effects of selenium on carcinogenesis during initiation and promotion

It is strongly believed that the major effects seen by selenium compounds in the latter stages of carcinogenesis can be ascribed to the prooxidative effects of selenium with redox cycling and ROS production as the main source of action [51]. The ROS production is a result of redox cycling of redox active selenium compounds with oxygen, resulting in a massive non stoichiometric production of mainly superoxide [52] with an altered and more oxidative redox balance (Fig. 2), which may eventually lead to cell death. The redox active selenium metabolites, like selenide, also cause thiol oxidation (Fig. 3). The oxidation of the structural cyteine residues leads to a thiol modification, which directly inhibits several proteins, including signalling molecules, enzymes, tumour suppressors and transcription factors. Among these are caspases, p53, AP-1, Sp1, NFkB, ASK-1 and JNK [53, 54, 55, 56]. The function of many of these proteins is in turn regulated through thiol modification by thioredoxin [57].
Fig. 3

Modification of protein thiols by selenium compounds

Redox active selenium compounds can all induce apoptosis, but their mechanism of action differs. Selenide induces a primarily caspase independent apoptosis generating DNA strand breaks, activation of p38, induction of p21 and p53. In addition selenide accumulates Bax and downregulates Bcl-2. Monomethylselenol on the other hand induces apoptosis in a caspase dependent manner, upregulating p21 and p16. Furthermore, selenide will cause arrest in S-phase wile treatment with monomethylselenol results in G1 arrest. Selenium compounds are also known to inhibit Erk, AR, Akt, cyclins, and CDKs, thus inhibiting cell cycle, growth and proliferation [58, 59].

The role of selenium during progression and metastasis

Several studies have shown that selenium compounds prevent tumour development during the progression phase of the carcinogenic process [60] and that these effects are tumour specific [61, 62]. A recent study show that the tumour specific effect of selenium can be explained by the extracellular redox environment, where a more reducing environment (often accounted for by the tumour cells) favours selenium uptake causing a tumour selective killing of the cell [13]. In addition selenium treatment can impair microvascular development [63] and affect the vascular endothelial growth factor (VEGF) and thereby contributing to anti-angiogenesis [64]. Through down regulation of genes such as osteopontin and collagen, selenium also counteracts metastasis [65, 66]. The tumour specific toxicity together with the anti-angiogenetic and anti-metastatic effects of selenium makes it a highly interesting agent in the arena of chemotherapy.

Concluding remarks

Selenium is unique among the antioxidants and a great body of evidence clearly show the potential of this element in large-scale general prevention of human cancers. Prevention is exerted through several different complex mechanisms and in all stages of the carcinogenic process. The chemical properties explain these effects where redox activity is the key factor. For this reason only redox active selenium compounds or precursors to these compounds are the only rational choice in prevention studies.

Future prevention strategies

Selenium compounds are generally cheap and in the correct dose harmless why selenium supplementation is an attractive and achievable way to reach decreased cancer incidences for the benefit of large groups of people worldwide. If only a fraction of the results indicated in the positive correctly performed trials could be reached in a large scale this would have a great impact to reduce healthcare expenses and human suffering.

Notes

Acknowledgment

This work was supported by grants from The Swedish Cancer Society, The Swedish Cancer and Allergy Foundation, Stockholm County Council and Radiumhemmets forskningsfonder.

References

  1. 1.
    Berzelius JJ. Undersökning af en ny mineral-kropp, funnen i de orenare sorterna af det vid Falun tillverkade svaflet. In: Afhandlingar i fysik, kemi och mineralogi ed^eds). Nordström Stockholm. 1818. p. 42–144.Google Scholar
  2. 2.
    Reddy BS, Hanson D, Mathews L, Sharma C. Effect of micronutrients, antioxidants and related compounds on the mutagenicity of 3, 2′-dimethyl-4-aminobiphenyl, a colon and breast carcinogen. Food Chem Toxicol. 1983;21:129–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Huber RE, Criddle RS. Comparison of the chemical properties of selenocysteine and selenocystine with their sulfur analogs. Arch Biochem Biophys. 1967;122:164–73.PubMedCrossRefGoogle Scholar
  4. 4.
    Butler JA, Beilstein MA, Whanger PD. Influence of dietary methionine on the metabolism of selenomethionine in rats. J Nutr. 1989;119:1001–9.PubMedGoogle Scholar
  5. 5.
    Berggren M, Gallegos A, Gasdaska JR, Gasdaska PY, Warneke J, Powis G. Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res. 1996;16:3459–66.PubMedGoogle Scholar
  6. 6.
    Suzuki KT, Kurasaki K, Suzuki N. Selenocysteine beta-lyase and methylselenol demethylase in the metabolism of Se-methylated selenocompounds into selenide. Biochim Biophys Acta. 2007;1770:1053–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Painter EP. The chemistry and toxicity of selenium compounds with special reference to the selenium problem. Chem Rev. 1941;28:179–213.CrossRefGoogle Scholar
  8. 8.
    Ganther HE, Corcoran C. Selenotrisulfides. II. Cross-linking of reduced pancreatic ribonuclease with selenium. Biochemistry. 1969;8:2557–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Ganther HE. Reduction of the selenotrisulfide derivative of glutathione to a persulfide analog by glutathione reductase. Biochemistry. 1971;10:4089–98.PubMedCrossRefGoogle Scholar
  10. 10.
    Björnstedt M, Kumar S, Holmgren A. Selenodiglutathione is a highly efficient oxidant of reduced thioredoxin and a substrate for mammalian thioredoxin reductase. J Biol Chem. 1992;267:8030–4.PubMedGoogle Scholar
  11. 11.
    Kumar S, Björnstedt M, Holmgren A. Selenite is a substrate for calf thymus thioredoxin reductase and thioredoxin and elicits a large non-stoichiometric oxidation of NADPH in the presence of oxygen. Eur J Biochem. 1992;207:435–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Wallenberg M, Olm E, Hebert C, Björnstedt M, Fernandes AP. Selenium compounds are substrates for glutaredoxins: A novel pathway for selenium metabolism and a potential mechanism for selenium mediated cytotoxicity. Biochemical Journal. 2010.Google Scholar
  13. 13.
    Olm E, Fernandes AP, Hebert C, Rundlof AK, Larsen EH, Danielsson O, et al. Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci U S A. 2009;106:11400–5.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Selenius M, Rundlof AK, Olm E, Fernandes AP, Bjornstedt M. Selenium and the selenoprotein thioredoxin reductase in the prevention, treatment and diagnostics of cancer. Antioxid Redox Signal. 2010;12:867–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Spallholz JE, Shriver BJ, Reid TW. Dimethyldiselenide and methylseleninic acid generate superoxide in an in vitro chemiluminescence assay in the presence of glutathione: implications for the anticarcinogenic activity of L-selenomethionine and L-Se-methylselenocysteine. Nutr Cancer. 2001;40:34–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, et al. Characterization of mammalian selenoproteomes. Science. 2003;300:1439–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Gladyshev VN, Kryukov GV. Evolution of selenocysteine-containing proteins: significance of identification and functional characterization of selenoproteins. Biofactors. 2001;14:87–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal. 2007;9:775–806.PubMedCrossRefGoogle Scholar
  19. 19.
    Tsuji Y, Suzuki N, TS K, Ogra Y. Selenium metabolism in rats with long-term ingestion of Se-methylselenocysteine using enriched stable isotopes. J Toxicol Sci. 2009;34:191–200.PubMedCrossRefGoogle Scholar
  20. 20.
    Ohta Y, Suzuki KT. Methylation and demethylation of intermediates selenide and methylselenol in the metabolism of selenium. Toxicol Appl Pharmacol. 2008;226:169–77.PubMedCrossRefGoogle Scholar
  21. 21.
    Clark LC, Combs Jr GF, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276:1957–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Schrauzer GN, White DA, Schneider CJ. Cancer mortality correlation studies-III: statistical associations with dietary selenium intakes. Bioinorg Chem. 1977;7:23–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Willett WC, Polk BF, Morris JS, Stampfer MJ, Pressel S, Rosner B, et al. Prediagnostic serum selenium and risk of cancer. Lancet. 1983;2:130–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Whanger PD. Selenium and its relationship to cancer: an update dagger. Br J Nutr. 2004;91:11–28.PubMedCrossRefGoogle Scholar
  25. 25.
    Bardia A, Tleyjeh IM, Cerhan JR, Sood AK, Limburg PJ, Erwin PJ, et al. Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis. Mayo Clin Proc. 2008;83:23–34.PubMedCrossRefGoogle Scholar
  26. 26.
    Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364:1219–28.PubMedCrossRefGoogle Scholar
  27. 27.
    Lopez-Saez JB, Senra-Varela A, Pousa-Estevez L. Selenium in breast cancer. Oncology. 2003;64:227–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Shamberger RJ, Willis CE. Selenium distribution and human cancer mortality. CRC Crit Rev Clin Lab Sci. 1971;2:211–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Pourmand G, Salem S, Moradi K, Nikoobakht MR, Tajik P, Mehrsai A. Serum selenium level and prostate cancer: a case-control study. Nutr Cancer. 2008;60:171–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Reid ME, Duffield-Lillico AJ, Slate E, Natarajan N, Turnbull B, Jacobs E, et al. The nutritional prevention of cancer: 400 mcg per day selenium treatment. Nutr Cancer. 2008;60:155–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Facompre N, El-Bayoumy K. Potential stages for prostate cancer prevention with selenium: implications for cancer survivors. Cancer Res. 2009;69:2699–703.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int. 2003;91:608–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Rayman MP. Selenoproteins and human health: insights from epidemiological data. Biochim Biophys Acta. 2009;1790:1533–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Yu SY, Zhu YJ, Li WG, Huang QS, Huang CZ, Zhang QN, et al. A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biol Trace Elem Res. 1991;29:289–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997;56:117–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301:39–51.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hatfield DL, Gladyshev VN. The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv. 2009;9:18–21.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Larsen EH, Hansen M, Paulin H, Moesgaard S, Reid M, Rayman M. Speciation and bioavailability of selenium in yeast-based intervention agents used in cancer chemoprevention studies. J AOAC Int. 2004;87:225–32.PubMedGoogle Scholar
  39. 39.
    Mahn AV, Munoz MC, Zamorano MJ. Discovery of biomarkers that reflect the intake of sodium selenate by nutritional proteomics. J Chromatogr Sci. 2009;47:840–3.PubMedCrossRefGoogle Scholar
  40. 40.
    Jackson MI, Combs Jr GF. Selenium and anticarcinogenesis: underlying mechanisms. Curr Opin Clin Nutr Metab Care. 2008;11:718–26.PubMedCrossRefGoogle Scholar
  41. 41.
    Hatfield DL, Yoo MH, Carlson BA, Gladyshev VN. Selenoproteins that function in cancer prevention and promotion. Biochim Biophys Acta. 2009;1790:1541–5.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Steinbrenner H, Sies H. Protection against reactive oxygen species by selenoproteins. Biochim Biophys Acta. 2009;1790:1478–85.PubMedCrossRefGoogle Scholar
  43. 43.
    Schrauzer GN. Selenium and selenium-antagonistic elements in nutritional cancer prevention. Crit Rev Biotechnol. 2009;29:10–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Dillard CJ, Tappel AL. Mercury, silver, and gold inhibition of selenium-accelerated cysteine oxidation. J Inorg Biochem. 1986;28:13–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Sugawara N, Sugawara C. Selenium protection against testicular lipid peroxidation from cadmium. J Appl Biochem. 1984;6:199–204.PubMedGoogle Scholar
  46. 46.
    Tatum L, Shankar P, Boylan LM, Spallholz JE. Effect of dietary copper on selenium toxicity in Fischer 344 rats. Biol Trace Elem Res. 2000;77:241–9.PubMedCrossRefGoogle Scholar
  47. 47.
    El-Bayoumy K, Sinha R. Molecular chemoprevention by selenium: a genomic approach. Mutat Res. 2005;591:224–36.PubMedCrossRefGoogle Scholar
  48. 48.
    Xiao H, Parkin KL. Induction of phase II enzyme activity by various selenium compounds. Nutr Cancer. 2006;55:210–23.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang H, Dong Y, Zhao H, Brooks JD, Hawthorn L, Nowak N, et al. Microarray data mining for potential selenium targets in chemoprevention of prostate cancer. Cancer Genomics Proteomics. 2005;2:97–114.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Mahn AV, Toledo HM, Ruz MH. Organic and inorganic selenium compounds produce different protein patterns in the blood plasma of rats. Biol Res. 2009;42:163–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Drake EN. Cancer chemoprevention: selenium as a prooxidant, not an antioxidant. Med Hypotheses. 2006;67:318–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Chen JJ, Boylan LM, Wu CK, Spallholz JE. Oxidation of glutathione and superoxide generation by inorganic and organic selenium compounds. Biofactors. 2007;31:55–66.PubMedCrossRefGoogle Scholar
  53. 53.
    Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radic Biol Med. 1997;22:1115–26.PubMedCrossRefGoogle Scholar
  54. 54.
    Zou Y, Niu P, Yang J, Yuan J, Wu T, Chen X. The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cells. Cancer Biol Ther. 2008;7:689–96.PubMedCrossRefGoogle Scholar
  55. 55.
    Ranawat P, Bansal MP. Decreased glutathione levels potentiate the apoptotic efficacy of selenium: possible involvement of p38 and JNK MAPKs–in vitro studies. Mol Cell Biochem. 2008;309:21–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Husbeck B, Bhattacharyya RS, Feldman D, Knox SJ. Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action. Mol Cancer Ther. 2006;5:2078–85.PubMedCrossRefGoogle Scholar
  57. 57.
    Arnér ES, Holmgren A. The thioredoxin system in cancer. Semin Cancer Biol. 2006;16:420–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Zhao H, Whitfield ML, Xu T, Botstein D, Brooks JD. Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells. Mol Biol Cell. 2004;15:506–19.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Dong Y, Ganther HE, Stewart C, Ip C. Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res. 2002;62:708–14.PubMedGoogle Scholar
  60. 60.
    Björkhem-Bergman L, Torndal UB, Eken S, Nyström C, Capitanio A, Larsen EH, et al. Selenium prevents tumor development in a rat model for chemical carcinogenesis. Carcinogenesis. 2005;26:125–31.PubMedCrossRefGoogle Scholar
  61. 61.
    Nilsonne G, Sun X, Nyström C, Rundlöf AK, Fernandes AP, Björnstedt M, et al. Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress. Free Radic Biol Med. 2006;41:874–85.PubMedCrossRefGoogle Scholar
  62. 62.
    Husbeck B, Nonn L, Peehl DM, Knox SJ. Tumor-selective killing by selenite in patient-matched pairs of normal and malignant prostate cells. Prostate. 2006;66:218–25.PubMedCrossRefGoogle Scholar
  63. 63.
    Yan L, Yee JA, McGuire MH, Graef GL. Effect of dietary supplementation of selenite on pulmonary metastasis of melanoma cells in mice. Nutr Cancer. 1997;28:165–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Jiang C, Ganther H, Lu J. Monomethyl selenium-specific inhibition of MMP-2 and VEGF expression: implications for angiogenic switch regulation. Mol Carcinog. 2000;29:236–50.PubMedCrossRefGoogle Scholar
  65. 65.
    Unni E, Kittrell FS, Singh U, Sinha R. Osteopontin is a potential target gene in mouse mammary cancer chemoprevention by Se-methylselenocysteine. Breast Cancer Res. 2004;6:R586–592.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yoon SO, Kim MM, Chung AS. Inhibitory effect of selenite on invasion of HT1080 tumor cells. J Biol Chem. 2001;276:20085–92.PubMedCrossRefGoogle Scholar

Copyright information

© European Association for Predictive, Preventive and Personalised Medicine 2010

Authors and Affiliations

  1. 1.Division of Pathology, Department of Laboratory Medicine, Karolinska InstitutetKarolinska University HospitalStockholmSweden

Personalised recommendations