**4. Pathophysiology of cancer and causes**

Cancer is a disease of regulation of tissue growth. In this disease, the cells of the body display uncontrolled growth, invasion that intrudes and destroys adjacent tissues and spreads to other body locations. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered and DNA repair genes are altered and turned off [53, 54]. The pathophysiology of cancer is a complicated issue. Genes that are influenced in the pathogenesis of cancer are proteins that are involved in a variety of processes including cell growth and differentiation, cell cycle processes, and angiogenesis, which is the formation of new blood vessels [55]. These proteins also play a role in tumour progression, immune regulation, and apoptosis. Since the cells involved are complex and have such a broad range of functions, the pathophysiology of cancer has been hard to determine precisely.

Understanding what causes cancer is a complex process. Cancer has been linked to many factors, such as environmental exposures, lifestyle practices, medical interventions, genetic traits, viruses, familial susceptibility, and aging. Cancer is most probably the result of inter‐ actions between repeated carcinogenic exposures and an individual's susceptibility status [56]. Environmental exposures and lifestyle practices have been determined to be the major risk factors in the development of cancer [57, 58]. The major lifestyle factors that contribute to cancer include smoking, alcohol, diet, medical practices, and ultraviolet exposures.

Genes that are influenced in the pathogenesis of lung cancer are proteins that are in‐ volved in a variety of processes including cell growth and differentiation, cell cycle processes, and angiogenesis, which is the formation of new blood vessels. The proteins also play a role in tumour progression, immune regulation, and apoptosis [59, 60]. Since the cells involved are complex and have such a broad range of functions, the pathophysiolo‐ gy of lung cancer has been hard to determine precisely. A healthy cell becomes a cancer cell by undergoing the following processes in which proto-oncogenes are changed to oncogenes. Proto-oncogenes are genes that are coded to maintain normal cell growth. In cases of a developing cancer, oncogene takes its place. Oncogene is a gene that makes cells grow and divide rapidly [61]. Pharmaceutical companies are continuing to develop approaches for targeting oncogene activity in the ongoing war on cancer [61]. Pathology of cancers and other complex disorders have undergone a big change after development of technologies like immunohistochemistry, flow cytometry, and molecular biologic ap‐ proaches to cancer diagnosis. Cancer is not a singular, specific disease but a group of variable tissue responses that result in uncontrolled cell growth [56].

### **5. Selenium mechanism**

harmless water. Of the eight known glutathione peroxidase enzymes, five of them require selenium. It is a necessary component for appropriate function of the immune system, muscle function, successful reproduction, and peak brain function. Also, selenium produces valuable antioxidant enzymes. Deficiencies in selenium have been linked to decreased thyroid function, cardiovascular disease, and cancers [24]. Research shows selenium, especially when used in conjunction with vitamin C, vitamin E and beta-carotene, works to block chemical reactions that create free radicals in the body (which can damage DNA and cause degenerative change in cells, leading to cancer). Also research has demonstrated that selenium is also linked to

Cancer is a disease of regulation of tissue growth. In this disease, the cells of the body display uncontrolled growth, invasion that intrudes and destroys adjacent tissues and spreads to other body locations. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered and DNA repair genes are altered and turned off [53, 54]. The pathophysiology of cancer is a complicated issue. Genes that are influenced in the pathogenesis of cancer are proteins that are involved in a variety of processes including cell growth and differentiation, cell cycle processes, and angiogenesis, which is the formation of new blood vessels [55]. These proteins also play a role in tumour progression, immune regulation, and apoptosis. Since the cells involved are complex and have such a broad range

Understanding what causes cancer is a complex process. Cancer has been linked to many factors, such as environmental exposures, lifestyle practices, medical interventions, genetic traits, viruses, familial susceptibility, and aging. Cancer is most probably the result of inter‐ actions between repeated carcinogenic exposures and an individual's susceptibility status [56]. Environmental exposures and lifestyle practices have been determined to be the major risk factors in the development of cancer [57, 58]. The major lifestyle factors that contribute to cancer

Genes that are influenced in the pathogenesis of lung cancer are proteins that are in‐ volved in a variety of processes including cell growth and differentiation, cell cycle processes, and angiogenesis, which is the formation of new blood vessels. The proteins also play a role in tumour progression, immune regulation, and apoptosis [59, 60]. Since the cells involved are complex and have such a broad range of functions, the pathophysiolo‐ gy of lung cancer has been hard to determine precisely. A healthy cell becomes a cancer cell by undergoing the following processes in which proto-oncogenes are changed to oncogenes. Proto-oncogenes are genes that are coded to maintain normal cell growth. In cases of a developing cancer, oncogene takes its place. Oncogene is a gene that makes cells grow and divide rapidly [61]. Pharmaceutical companies are continuing to develop approaches for targeting oncogene activity in the ongoing war on cancer [61]. Pathology of cancers and other complex disorders have undergone a big change after development of

of functions, the pathophysiology of cancer has been hard to determine precisely.

include smoking, alcohol, diet, medical practices, and ultraviolet exposures.

reduction in risk to some carcinomas [6, 7].

**4. Pathophysiology of cancer and causes**

298 Pharmacology and Nutritional Intervention in the Treatment of Disease

The biochemistry of selenium differs from other dietary minerals and trace elements. Selenium is not a structural component nor a metal coordination complex and the biosynthesis of selenocysteine is regulated by four genes and begins with the aminoacylation of the amino acid serine by the enzyme serine synthetase to produce Ser-tRNASec [62, 63]. However, selenocysteine is the active site in which, at physiological pH, selenium is fully ionized and is a very efficient redox catalyst [64]. Selenium exists in elemental, organic, and inorganic forms, with four important oxidation states: selenide (Se 2−), elemental (Se0) selenite (Se+4), and selenate (Se+6) [62, 65]. Selenium compounds inhibit signaling enzymes such as protein kinase C (PKC) [66] that play crucial roles in tumor promotion. The selenium-containing nutrient, selenomethionine has been shown to regulate the tumor suppresser p53 by the redox factor refl-dependent redox mechanism. Studies continue to support evidence that one important pathway is that many selenium-containing nutrients can be converted in the body to methyl‐ selenol. Methylselenol has been shown to block expansion of pre-malignant cells forming into fully developed cancers [67]. Several pathways have been proposed that could explain how selenium-containing compounds could block mutated cells from progressing to cancer. Methylseleninic acid has been shown to inhibit NF-kappa B and regulate I kappa B in prostate cancer cells [68]. Selenium compounds inhibit signaling enzymes such as protein kinase C (PKC) [66] that play crucial roles in tumor promotion. A representative of the hydrogen selenide metabolic pool has been found to protect liver cells against damage to DNA. The cellular redox-milieu involves several metabolic, antioxidative and regulatory aspects that are maintained and regulated largely by two enzyme-based systems: the glutathione and thiore‐ doxin systems [69] The thioredoxin and glutathione systems constitute a balanced redox network. The thioredoxin system may influence virtually all phases of tumorgenesis via its involvement in transcription and translation [69].

There are several possible mechanisms for the protective effect of selenium. Selenium activates an enzyme in the body called glutathione peroxidase that protects against the formation of free radicals—those loose molecular cannons that can damage DNA. There appear to be at least two distinct families of selenium-containing enzymes [70, 71]. The first includes gluta‐ thione peroxidases Bermano et al [72] and thioredoxin reductase [73], which are involved in controlling tissue concentrations of highly reactive oxygen-containing metabolites. These metabolites are essential at low concentrations for maintaining cell-mediated immunity against infections but highly toxic if produced in excess.

The role of selenium in the cytosolic enzyme glutathione peroxidase (GPx) was first illustrated [74, 75]. During stress, infection, or tissue injury, selenoenzymes may protect against the damaging effects of hydrogen peroxide or oxygen-rich free radicals. This family of enzymes catalyses the destruction of hydrogen peroxide or lipid hydroperoxides according to the following general reactions:

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 equivalents

$$\begin{aligned} \text{H}\_2\text{O}\_2 + 2\text{GSH} \cdot \text{---} &\cdots \cdot 2\text{H}\_2\text{O} + \text{GSSG} \\ \text{ROOH} + 2\text{GSH} \cdot \text{---} &\cdots \cdot \text{ROH} + \text{H}\_2\text{O} + \text{GSSG} \end{aligned} \tag{1}$$

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

The Pharmacology and Biochemistry of Selenium in Cancer

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

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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.

affected by antioxidant supplementation [88].

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 and tissue atrophy [76].

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 glutathione peroxidase:
