Methyl selenocysteine

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Alternative Cancer Treatment - Articles Methyl Selenocysteine Although Methylselenocysteine is one of the most biologically active, and cancer inhibitory and preventive Se compounds, the less active SeMet and selenite are the Se forms currently available in the majority of nutritional supplements. It has become increasingly evident that dietary Se plays a significant role in reducing the incidence of lung, colorectal and prostate cancer in humans. Different forms of Se vary in their chemopreventative efficacy, with Se-methylselenocysteine being one of the most potent. Interestingly, the Se accumulating plant Astragalus bisulcatus (Two-grooved poison vetch) contains up to 0.6% of its shoot dry weight as Se-methylselenocysteine. The ability of this Se accumulator to biosynthesize Se-methylselenocysteine provides a critical metabolic shunt that prevents selenocysteine and selenomethionine from entering the protein biosynthetic machinery. Such a metabolic shunt has been proposed to be vital for Se tolerance in A. bisulcatus. Utilization of this mechanism in other plants may provide a possible avenue for the genetic engineering of Se tolerance in plants ideally suited for the phytoremediation of Se contaminated land. Here, we describe the overexpression of a selenocysteine methyltransferase from A. bisulcatus to engineer Se-methylselenocysteine metabolism in the Se non-accumulator Arabidopsis thaliana (Thale cress). Results By over producing the A. bisulcatus enzyme selenocysteine methyltransferase in A. thaliana, we have introduced a novel biosynthetic ability that allows the non-accumulator to accumulate Se-methylselenocysteine and γ-glutamylmethylselenocysteine in shoots. The biosynthesis of Se-methylselenocysteine in A. thaliana also confers significantly increased selenite tolerance and foliar Se accumulation. Conclusion These results demonstrate the feasibility of developing transgenic plant-based production of Se-methylselenocysteine, as well as bioengineering selenite resistance in plants. Selenite resistance is the first step in engineering plants that are resistant to selenate, the predominant form of Se in the environment. Selenium is an essential nutrient for animals, microorganisms and some other eukaryotes [1]. While Se deficiency is rare in the US, it does occur in several low Se parts of the world such as China, and can lead to heart disease, hypothyroidism and a weakened immune system [2,3]. The toxic effects of excess Se have been known for some time. Short-term consumption of high levels of Se may cause nausea, vomiting, and diarrhea, whereas chronic consumption of high concentrations of Se compounds can result in a disease called selenosis [4]. Only one form of Se, selenium sulfide, has been implicated as a carcinogen [4]. The recognition of Se bioaccumulation and resulting wildlife toxicity at Kesterson reservoir in California and other sites has resulted in a surge of interest in phytoremediation of Se [5-8]. Selenium in the environment can be the result of either natural geological processes or human activities. The USGS has identified 160,000 miles2 of land in the western US enriched in Se from natural processes that is susceptible to irrigation-induced Se contamination, including 4,100 miles2 of land currently irrigated for agriculture [9]. Selenium pollution can also arise from various industrial and manufacturing processes including procurement, processing, and combustion of fossil fuels [10], and mining [11]. Interestingly, in the last decade it has become increasingly evident that Se also has potential health benefits. Anticarcinogenic activities of specific organic forms of Se against certain types of cancer have been demonstrated [3,12-14]. In a long term, double-blind study, supplemental dietary Se was associated with significant reductions in lung, colorectal and prostate cancer in humans [3]. Other studies have also demonstrated the chemoprotective effects of Se against breast, liver, prostate, and colorectal cancers in model systems [15-17]. Importantly, there is a great deal of variation in the efficacy of different Se compounds against cancer [13,18]. Numerous studies have demonstrated the efficacy of Se-methylselenocysteine (MeSeCys) in preventing mammary cancer in rat model systems [16,19-23], and importantly, MeSeCys has been shown to be twice as active as Se-methionine (the primary component of Se-yeast supplements) in preventing the development of mammary tumors in rats [18]. Furthermore, MeSeCys in both garlic and broccoli has also been shown to be more effective than either Se-methionine (SeMet) in yeast, or broccoli supplemented with selenite, at reducing both the incidence of mammary and colon cancer in rats [19,21]. This nonprotein seleno amino acid is produced in certain plants including members of the Brassica and Allium genera [3,24], and in Se accumulating plants such as Astragalus bisulcatus [25,26]. While the specific mechanism for the anticancer activity of Se has not been fully elucidated, multiple studies have demonstrated the ability of Se to affect the cell cycle and induce apoptosis in cancer cell lines [14,24,27-35]. There is also evidence that Se may inhibit tumor angiogenesis [36,37]. Both of these activities would inhibit progression of early cancerous lesions. Plants primarily take up Se as selenate or selenite [38], which is then metabolized, via the sulfur assimilation pathway, resulting in the production of selenocysteine, SeMet and other Se analogues of various S metabolites, as reviewed by Ellis and Salt (2003) [39]. The nonspecific incorporation of seleno amino acids into proteins is thought to contribute to Se toxicity [40]. One proposed mechanism of Se tolerance in plants is the specific conversion of potentially toxic seleno amino acids into nonprotein derivatives such as MeSeCys [41,42]. Some Brassica and Allium species, when grown in Se enriched medium, can accumulate 0.1–2.8 μmol g-1 dry weight MeSeCys or its functional equivalent γ-glutamylmethylselenocysteine (γGluMeSeCys) [13,15,16,21,24,43]. However, certain specialized Se accumulating plants, such as A. bisulcatus, accumulate up to 68 μmol g-1 dry weight Se (6000 μg g-1 dry weight), of which 90–95% is MeSeCys in young leaves [44-46]. Selenocysteine methyltransferase (SMT), the enzyme responsible for the methylation of selenocysteine to MeSeCys in A. bisulcatus, has recently been cloned and characterized [47]. The availability of such genetic material opens a practical avenue for the development of plants with an enhanced ability to biosynthesize MeSeCys. Such plants would be expected to not only be more resistant to Se, a valuable trait for phytoremediation of Se contaminated land, but also provide a plant based source of the anticarcongenic compound MeSeCys [44]. Here, we describe the successful use of A. bisulcatus genetic material to engineer MeSeCys metabolism in the Se non-accumulator A. thaliana. By over-producing the A. bisulcatus enzyme SMT in A. thaliana, we have introduced a novel biosynthetic ability that has increased the concentration of MeSeCys and its functional derivative γGluMeSeCys, from essentially non-detectable levels in the leaves of wild-type A. thaliana up to 3.9 μmol g-1 dry weight in shoots. Selenium Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA). Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. OBJECTIVES: Epidemiological studies and prevention trials suggest selenium is a promising preventive agent for prostate cancer. Selenium-containing compounds inhibited the growth of prostate cancer cell lines including androgen sensitive LNCaP and androgen insensitive DU145 and PC3 cells in vitro. Previous study revealed a novel mechanism of selenium action in which selenium (methylseleninic acid (MSA)) markedly reduced androgen receptor (AR) signaling in prostate cancer cells, suggesting that selenium might act as an antiandrogen, which could serve as a therapeutic agent for prostate cancer. In this study, we tested whether selenium (methylselenocysteine (MSC)) affects tumor growth of human prostate cancer cells by targeting AR signaling in vivo. METHODS: Prostate tumor xenografts were established in nude mice by co-inoculating LNCaP cells with Matrigel. The mice-bearing tumors were treated with or without MSC (100 microg/mouse/day) via intraperitoneal injection for 2 weeks. The effect of MSC on tumor growth, AR, and prostate-specific antigen (PSA) expression was examined. RESULTS: Methylselenocysteine (MSC) significantly inhibited LNCaP tumor growth (P < 0.05). AR expression in tumor tissues and serum PSA levels were considerably decreased in MSC-treated mice compared to the vehicle controls. CONCLUSIONS: Pharmacological dose of MSC inhibits the growth of LNCaP human prostate cancer in vivo accompanied by a decrease in the expression of AR and PSA. These findings suggest that selenium (MSC) can serve as a therapeutic agent aimed at disruption of AR signaling for prostate cancer. Copyright 2005 Wiley-Liss, Inc. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. L. C. Clark, G. F. Combs Jr, B. W. Turnbull, E. H. Slate, D. K. Chalker, J. Chow, L. S. Davis, R. A. Glover, G. F. Graham, E. G. Gross, A. Krongrad, J. L. Lesher Jr, H. K. Park, B. B. Sanders Jr, C. L. Smith and J. R. Taylor *Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, USA* OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made. Contact The Institute for Healthy Aging 101 NW 1st Avenue delray beach, fl 33444 Telephone 561 272 1956 Fax 561 272 1992 E-mail: bnelson@antiagemed.com http://www.antiagemed.com/
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Methyl Selenocysteine

Although Methylselenocysteine is one of the most biologically active, and cancer inhibitory and preventive Se compounds, the less active SeMet and selenite are the Se forms currently available in the majority of nutritional supplements.

It has become increasingly evident that dietary Se plays a significant role in reducing the incidence of lung, colorectal and prostate cancer in humans. Different forms of Se vary in their chemopreventative efficacy, with Se-methylselenocysteine being one of the most potent. Interestingly, the Se accumulating plant Astragalus bisulcatus (Two-grooved poison vetch) contains up to 0.6% of its shoot dry weight as Se-methylselenocysteine. The ability of this Se accumulator to biosynthesize Se-methylselenocysteine provides a critical metabolic shunt that prevents selenocysteine and selenomethionine from entering the protein biosynthetic machinery. Such a metabolic shunt has been proposed to be vital for Se tolerance in A. bisulcatus. Utilization of this mechanism in other plants may provide a possible avenue for the genetic engineering of Se tolerance in plants ideally suited for the phytoremediation of Se contaminated land. Here, we describe the overexpression of a selenocysteine methyltransferase from A. bisulcatus to engineer Se-methylselenocysteine metabolism in the Se non-accumulator Arabidopsis thaliana (Thale cress).

Results

By over producing the A. bisulcatus enzyme selenocysteine methyltransferase in A. thaliana, we have introduced a novel biosynthetic ability that allows the non-accumulator to accumulate Se-methylselenocysteine and γ-glutamylmethylselenocysteine in shoots. The biosynthesis of Se-methylselenocysteine in A. thaliana also confers significantly increased selenite tolerance and foliar Se accumulation.

Conclusion

These results demonstrate the feasibility of developing transgenic plant-based production of Se-methylselenocysteine, as well as bioengineering selenite resistance in plants. Selenite resistance is the first step in engineering plants that are resistant to selenate, the predominant form of Se in the environment.

Selenium is an essential nutrient for animals, microorganisms and some other eukaryotes [1]. While Se deficiency is rare in the US, it does occur in several low Se parts of the world such as China, and can lead to heart disease, hypothyroidism and a weakened immune system [2,3]. The toxic effects of excess Se have been known for some time. Short-term consumption of high levels of Se may cause nausea, vomiting, and diarrhea, whereas chronic consumption of high concentrations of Se compounds can result in a disease called selenosis [4]. Only one form of Se, selenium sulfide, has been implicated as a carcinogen [4]. The recognition of Se bioaccumulation and resulting wildlife toxicity at Kesterson reservoir in California and other sites has resulted in a surge of interest in phytoremediation of Se [5-8]. Selenium in the environment can be the result of either natural geological processes or human activities. The USGS has identified 160,000 miles2 of land in the western US enriched in Se from natural processes that is susceptible to irrigation-induced Se contamination, including 4,100 miles2 of land currently irrigated for agriculture [9]. Selenium pollution can also arise from various industrial and manufacturing processes including procurement, processing, and combustion of fossil fuels [10], and mining [11].

Interestingly, in the last decade it has become increasingly evident that Se also has potential health benefits. Anticarcinogenic activities of specific organic forms of Se against certain types of cancer have been demonstrated [3,12-14]. In a long term, double-blind study, supplemental dietary Se was associated with significant reductions in lung, colorectal and prostate cancer in humans [3]. Other studies have also demonstrated the chemoprotective effects of Se against breast, liver, prostate, and colorectal cancers in model systems [15-17]. Importantly, there is a great deal of variation in the efficacy of different Se compounds against cancer [13,18]. Numerous studies have demonstrated the efficacy of Se-methylselenocysteine (MeSeCys) in preventing mammary cancer in rat model systems [16,19-23], and importantly, MeSeCys has been shown to be twice as active as Se-methionine (the primary component of Se-yeast supplements) in preventing the development of mammary tumors in rats [18]. Furthermore, MeSeCys in both garlic and broccoli has also been shown to be more effective than either Se-methionine (SeMet) in yeast, or broccoli supplemented with selenite, at reducing both the incidence of mammary and colon cancer in rats [19,21]. This nonprotein seleno amino acid is produced in certain plants including members of the Brassica and Allium genera [3,24], and in Se accumulating plants such as Astragalus bisulcatus [25,26]. While the specific mechanism for the anticancer activity of Se has not been fully elucidated, multiple studies have demonstrated the ability of Se to affect the cell cycle and induce apoptosis in cancer cell lines [14,24,27-35]. There is also evidence that Se may inhibit tumor angiogenesis [36,37]. Both of these activities would inhibit progression of early cancerous lesions.

Plants primarily take up Se as selenate or selenite [38], which is then metabolized, via the sulfur assimilation pathway, resulting in the production of selenocysteine, SeMet and other Se analogues of various S metabolites, as reviewed by Ellis and Salt (2003) [39]. The nonspecific incorporation of seleno amino acids into proteins is thought to contribute to Se toxicity [40]. One proposed mechanism of Se tolerance in plants is the specific conversion of potentially toxic seleno amino acids into nonprotein derivatives such as MeSeCys [41,42]. Some Brassica and Allium species, when grown in Se enriched medium, can accumulate 0.1–2.8 μmol g-1 dry weight MeSeCys or its functional equivalent γ-glutamylmethylselenocysteine (γGluMeSeCys) [13,15,16,21,24,43]. However, certain specialized Se accumulating plants, such as A. bisulcatus, accumulate up to 68 μmol g-1 dry weight Se (6000 μg g-1 dry weight), of which 90–95% is MeSeCys in young leaves [44-46].

Selenocysteine methyltransferase (SMT), the enzyme responsible for the methylation of selenocysteine to MeSeCys in A. bisulcatus, has recently been cloned and characterized [47]. The availability of such genetic material opens a practical avenue for the development of plants with an enhanced ability to biosynthesize MeSeCys. Such plants would be expected to not only be more resistant to Se, a valuable trait for phytoremediation of Se contaminated land, but also provide a plant based source of the anticarcongenic compound MeSeCys [44]. Here, we describe the successful use of A. bisulcatus genetic material to engineer MeSeCys metabolism in the Se non-accumulator A. thaliana. By over-producing the A. bisulcatus enzyme SMT in A. thaliana, we have introduced a novel biosynthetic ability that has increased the concentration of MeSeCys and its functional derivative γGluMeSeCys, from essentially non-detectable levels in the leaves of wild-type A. thaliana up to 3.9 μmol g-1 dry weight in shoots.

Selenium

Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA).

Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

OBJECTIVES: Epidemiological studies and prevention trials suggest selenium is a promising preventive agent for prostate cancer. Selenium-containing compounds inhibited the growth of prostate cancer cell lines including androgen sensitive LNCaP and androgen insensitive DU145 and PC3 cells in vitro. Previous study revealed a novel mechanism of selenium action in which selenium (methylseleninic acid (MSA)) markedly reduced androgen receptor (AR) signaling in prostate cancer cells, suggesting that selenium might act as an antiandrogen, which could serve as a therapeutic agent for prostate cancer. In this study, we tested whether selenium (methylselenocysteine (MSC)) affects tumor growth of human prostate cancer cells by targeting AR signaling in vivo. METHODS: Prostate tumor xenografts were established in nude mice by co-inoculating LNCaP cells with Matrigel. The mice-bearing tumors were treated with or without MSC (100 microg/mouse/day) via intraperitoneal injection for 2 weeks. The effect of MSC on tumor growth, AR, and prostate-specific antigen (PSA) expression was examined. RESULTS: Methylselenocysteine (MSC) significantly inhibited LNCaP tumor growth (P < 0.05). AR expression in tumor tissues and serum PSA levels were considerably decreased in MSC-treated mice compared to the vehicle controls. CONCLUSIONS: Pharmacological dose of MSC inhibits the growth of LNCaP human prostate cancer in vivo accompanied by a decrease in the expression of AR and PSA. These findings suggest that selenium (MSC) can serve as a therapeutic agent aimed at disruption of AR signaling for prostate cancer. Copyright 2005 Wiley-Liss, Inc.

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

L. C. Clark, G. F. Combs Jr, B. W. Turnbull, E. H. Slate, D. K. Chalker, J. Chow, L. S. Davis, R. A. Glover, G. F. Graham, E. G. Gross, A. Krongrad, J. L. Lesher Jr, H. K. Park, B. B. Sanders Jr, C. L. Smith and J. R. Taylor
Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, USA

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made.

ALTERNATIVE CANCER SOLUTION

Alternative Cancer Treatment - Articles