**6. Selenium function**

Despite an evident progress in cancer diagnosis and treatment, there is a constant need of a drug which could arrest the premalignant process, thus reducing the risk of cancer. However, the role of selenium (Se) as an antioxidant and anticancer agent is well documented [80]. In addition, it has been proven that an adequate concentration of selenium can restore the sensitivity to chemotherapeutic agents of cytostatic-resistant malignant cells [81]. Selenium can exist with oxidation state-2,+2,+4,+6, and Se (II) is the dominant form in organoselenium chemistry [82]. The highest activity as a free radical scavenger and anticancer agent is assigned to selenium compounds containing selenium at the+4 oxidation level [83]. Other essential role of selenium in human and animal nutrition is well established. In humans, it has been demonstrated that an endemic cardiomyopathy (Keshan disease) prevalent in certain areas of China is correlated with selenium deficiency [84, 85]. Selenium is often thought to be a dietary antioxidant, but the antioxidant effects of selenium are most likely due to the antioxidant activity of proteins that have this element as an essential component (i.e., selenium-containing proteins), and not to selenium itself [86]. The damage to cells caused by free radicals, especially the damage to DNA, may play a role in the development of cancer and other health conditions [40]. Many observational studies, including case–control studies and cohort studies, have been conducted to investigate whether the use of dietary antioxidant supplements is associated with reduced risks of cancer in humans. Overall, these studies have yielded mixed results [87]. Healthy Chinese men and women at increased risk of developing esophageal cancer and gastric cancer were randomly assigned to take a combination of 15 milligrams (mg) betacarotene, 30 mg α-tocopherol, and 50 micrograms (µg) selenium daily for 5 years or to take no antioxidant supplements. The initial results of the trial showed that people who took antiox‐ idant supplements had a lower risk of death from gastric cancer but not from oesophageal cancer. However, their risks of developing gastric cancer and/or esophageal cancer were not affected by antioxidant supplementation [88].

catalyses the destruction of hydrogen peroxide or lipid hydroperoxides according to the

Selenium-containing glutathione peroxidases (GPx) constitute a family of anti-oxidative enzymes that are capable of reducing organic and inorganic hydroperoxides to the corre‐ sponding hydroxy compounds utilizing glutathione or other hydrogen donors as reducing

Where GSH is glutathione and GSSG is its oxidized form. At least four forms of GPx exist; they differ both in their tissue distribution and in their sensitivity to selenium depletion [72]. The GPx enzymes of liver and blood plasma fall in activity rapidly at early stages of selenium deficiency. In contrast, a form of GPx associated specifically with phospholipid-rich tissue membranes is preserved against selenium deficiency and is believed to have broader metabolic roles (e.g., in prostaglandin synthesis) [76]. In concert with vitamin E, selenium is also involved in the protection of cell membranes against oxidative damage. The selenoenzyme thioredoxin reductase is involved in disposal of the products of oxidative metabolism [77]. It contains two selenocysteine groups per molecule and is a major component of a redox system with a multiplicity of functions, among which is the capacity to degrade locally excessive and potentially toxic concentrations of peroxide and hydroperoxides likely to induce cell death

There is strong evidence that oxidative free radicals have a role in the development of degenerative diseases including CHD [78]. Oxidative free radicals increase the peroxidation of low density lipoprotein thereby increasing its uptake by macrophages with increased foam cell formation and atherosclerosis [79], though other mechanisms may exist. Anti-oxidants in the diet include vitamin A (carotenoids, which are metabolised to retinol), vitamin C (ascor‐ bate), vitamin E (tocopherol), and selenium, which is an integral part of the antioxidant enzyme

Despite an evident progress in cancer diagnosis and treatment, there is a constant need of a drug which could arrest the premalignant process, thus reducing the risk of cancer. However, the role of selenium (Se) as an antioxidant and anticancer agent is well documented [80]. In addition, it has been proven that an adequate concentration of selenium can restore the sensitivity to chemotherapeutic agents of cytostatic-resistant malignant cells [81]. Selenium can exist with oxidation state-2,+2,+4,+6, and Se (II) is the dominant form in organoselenium chemistry [82]. The highest activity as a free radical scavenger and anticancer agent is assigned to selenium compounds containing selenium at the+4 oxidation level [83]. Other essential role of selenium in human and animal nutrition is well established. In humans, it has been

2

×××××××××××× (1)

2 2 2

H O + 2GSH 2H O + GSSG ROOH + 2GSH ROH + H O + GSSG

××××××××××××××

following general reactions:

300 Pharmacology and Nutritional Intervention in the Treatment of Disease

and tissue atrophy [76].

glutathione peroxidase:

**6. Selenium function**

equivalents

As an essential trace element in humans [89], it's only established function is its presence in the enzyme glutathione peroxidase [90]. Using GSH2 as the reducing equivalent, this enzyme plays a significant role in detoxification of peroxides induced by oxygen radicals. As such it may be important in the toxicity of anticancer treatments that generate such reactive molecules [91]. In addition, epidemiological and experimental data suggest an anti-carcinogenic activity by selenium [92]. Considerable epidemiological data suggests that cancer mortality is inversely correlated with selenium consumption. Chemoprotective effect of diphenylmethyl selenocya‐ nate against cyclophosphamide (CP) induced cellular toxicity and antitumor efficacy was evaluated in mice bearing Ehrlich ascites carcinoma [93], their results indicate that diphenyl‐ methyl selenocyanate has the potential to reduce the cellular toxicity of CP at the same time improving its antitumor efficacy. Supplementation of a torula yeast-based diet with 2.5 or 5.0 ppm Selenium as Na2SeO3 also significantly increased the survival time of EAT-bearing mice [94]. Their data show that the form and mode of administration of selenium influence the antitumorigenic properties of this trace element. In addition, they suggested that some intermediate in the normal pathway for selenium detoxification is probably responsible for this trace element's antitumorigenic properties [94]. The ability of selenium to inhibit or prevent the growth of Ehrlich as cites tumour cells was highly dependent upon the form and quantity of selenium administered [95]. The only significant alteration that has been observed in mice treated with quantities of selenium at dosages of 4µg 3 times weekly was a slight reduction in intestinal weights. The reduction in intestinal weights was not attributable to a reduction in the intestinal macro constituents, suggesting that selenium may have altered rapidly dividing cells [95]. In fact selenocystine was used in the treatment of human leukaemia in 1956 with some short term success [96, 97]. The mechanism of its effect was thought to be competitive deprivation of cystine, but this was not proven. Others have shown that selenium compounds can cause chromosome breaks and inhibit critical DNA synthetic enzymes [98]. Specific incorporation of selenium into RNA molecules has been observed in several bacterial species. Since in a number of instances modified bases in RNAs have been shown to be involved in regulatory functions of the RNAs, the selenium-modified bases may have similar roles. Furthermore, some RNA viruses, as well as leader mRNAs contain RNA-like segments that may interact with specific enzymes and, thus, play regulatory roles [99]. Hence, it is reasonable to assume that detailed information concerning selenium-modified RNAs may contribute to the understanding of the biological roles of selenium [100]. Near toxic levels of selenium have been reported to produce tumours in rats but other studies indicated that these concentrations of selenium created chronic toxic hepatitis that resembled hyperplasia.

up in lysosomes in macrophages, the deposits are essentially long lived or permanent [114]. A lack of positive effect of Se supplementation on the prostate cancer incidence was observed

The Pharmacology and Biochemistry of Selenium in Cancer

http://dx.doi.org/10.5772/58425

303

Selenium as non-metals is an essential nutrient that acts as cofactor in enzyme oxidation– reduction reactions. It maintains the specific configurations of proteins, is incorporated into the structure of hormones, and plays a structural and catalytic role in gene expression and transcriptional regulation. In the physiological dosage range, Se appears to function as an antimutagenic agent, preventing the malignant transformation of normal cells and the activation of oncogenes. These protective effects of Se seem to be primarily associated with its presence in the glutathione peroxidases, which are known to protect DNA and other cellular components from damage by oxygen radicals. Selenoenzymes are also known to play roles in carcinogen metabolism, in the control of cell division, oxygen metabolism, detoxification processes, apoptosis induction and the functioning of the immune system. Other modes of action, either direct or indirect, may also be operative, such as the partial retransformation of

and Faik Atroshi3

[1] WHO, World Health Organization. The Global Burden of Disease: 2004 Update. Gen‐

[2] Meyskens, F. L., Jr., & Szabo, E. Diet and cancer: the disconnect between epidemiolo‐ gy and randomized clinical trials. Cancer Epidemiol Biomarkers Prev, 2005, 14(6),

\*Address all correspondence to: tuomas.westermarck@ppa.inet.fi

3 Pharmacology & Toxicology, University of Helsinki, Finland

in this study.

**7. Conclusion**

**Author details**

**References**

1366-1369.

T. Westermarck1\*, Arno Latvus2

tumor cells and the inactivation of oncogenes.

1 Rinnekoti Research Center, Espoo, Finland

2 Hankintatukku Oy, Museokatu, Helsinki, Finland

eva: World Health Organization; 2008.

In mammals glutathione peroxidase is the only selenium-dependent enzyme so far identified, but it seems unlikely that the complicated biological effects of selenium in man and animals are attributable solely to variations in the level of this enzyme. In fact, at least two other seleno proteins of unknown catalytic activity have been detected in animals. Investigations in a variety of animal systems have suggested that there is a significant interaction of selenium with glutathione independent of the enzyme glutathione peroxidase [101]. White muscle disease (WMD), a degenerative muscle disease, found in domestic animals [102, 103]. It is caused by a deficiency of selenium and/or vitamin E. Selenium and vitamin E deficiencies can produce symptoms of ill thrift and reproductive losses: lower conception rates, fetal reabsorp‐ tion, dystocia, retained placenta, reduced milk production, and reduced semen quality, poor rate of growth or ill thrift in young lambs, low wool yields and have increased incidence of periodontal disease [102, 103]. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibition of HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases [104]. Studies continue to confirm that people with higher levels of selenium in their blood have lower rates of prostate and lung cancers [105].

Selenium is synergistic with vitamin E; they serve related metabolic functions and share in common the role of endogenous antioxidants [106]. Vitamin E has a free radical Scavenger, and Se as a component of the peroxide reducing enzyme, glutathione peroxidase. Vitamin E restricts the formation of peroxides by neutralizing free radicals, an integral component of glutathione peroxidase, an enzyme responsible for the removal of hydrogen peroxide and organic hydroperoxides [107].

Selenium and vitamin C; CH3SeH is thought to be a critical metabolite in Se chemoprevention [108, 109]. The family of selenoenzymes called thioredoxin reductases catalyze the NADPHdependent reduction of oxidized thioredoxin, hyperoxides, dehydroascorbate, ubiquinol and other substrates [110].The action of thioredoxin reductases in recycling dehydroascorbate to ascorbate (vitamin C) now explain the synergistic action of selenium and vitamin C [111]. The thioredoxin system is also capable of regenerating proteins inactivated by ROS. Daily supple‐ mentation with vitamin C (120 mg), vitamin E (30 mg), beta-carotene (6 mg), and the minerals selenium (100 µg) and zinc (20 mg) for a median of 7.5 years had no effect on the incidence of cancer or cardiovascular disease or on all-cause mortality [112]. Antioxidant and mineral supplementation was associated with lower total cancer incidence and all-cause mortality among men but not among women, and with an increase in skin cancer incidence, including melanoma, among women but not among men [113].

Selenium and Silver; Selenium serves as a major protective factor in precipitating the silver in a highly insoluble and hence inert form of silver selenide. Although some of this may be taken up in lysosomes in macrophages, the deposits are essentially long lived or permanent [114]. A lack of positive effect of Se supplementation on the prostate cancer incidence was observed in this study.
