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In Vitro and in Vivo Studies of Methylseleninic Acid: Evidence That a Monomethylated Selenium Metabolite Is Critical for Cancer Chemoprevention1

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In Vitro and in Vivo Studies of Methylseleninic Acid: Evidence That a Monomethylated Selenium Metabolite Is Critical for Cancer Chemoprevention1 [CANCER RESEARCH 60, 2882–2886, June 1, 2000] In Vitro and in Vivo Studies of Methylseleninic Acid: Evidence That a Monomethylated Selenium Metabolite Is Critical for Cancer Chemoprevention1 Clement Ip,2 Henry J. Thompson, Zongjian Zhu, and Howard E. Ganther Department of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263 [C. I.]; Center for Nutrition in the Prevention of Disease, AMC Cancer Research Center, Denver, Colorado 80214 [H. J. T., Z. Z.]; and Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706 [H. E. G.] ABSTRACT selenium to specific locations along the methylation pathway (3, 4). By this approach, we hoped to be able to pinpoint more closely the ␤ Previous research suggested that the -lyase-mediated production of a key metabolite that is involved in cancer protection. We found that monomethylated selenium metabolite from Se-methylselenocysteine is a any precursor that will directly generate a steady stream of methyl- key step in cancer chemoprevention by this agent. In an attempt to affirm the concept, the present study was designed to evaluate the activity of selenol is more active than selenite or selenomethionine in tumor methylseleninic acid, a compound that represents a simplified version of inhibition (5, 6). Thus, the facile endogenous production of mono- Se-methylselenocysteine without the amino acid moiety, thereby obviating methylated selenium is a critical factor in selenium chemoprevention. the need for ␤-lyase action. The in vitro experiments showed that meth- It should be noted that methylselenol is highly reactive and cannot be ylseleninic acid was more potent than Se-methylselenocysteine in inhibit- tested as is. ing cell accumulation and inducing apoptosis in TM12 (wild-type p53) and Se-methylselenocysteine, a lower homologue of selenomethionine, TM2H (nonfunctional p53) mouse mammary hyperplastic epithelial cells, is one such compound that meets the criteria of a good precursor for and these effects were not attributable to DNA damage, as determined by generating methylselenol. Instead of entering the multistep transsul- the comet assay. In general, methylseleninic acid produced a more robust furation pathway used by selenomethionine, Se-methylselenocysteine response at one-tenth the concentration of Se-methylselenocysteine. It is ␤ possible that these cell lines may have only a modest ability to generate a is acted upon immediately by the -lyase enzyme to produce meth- monomethylated selenium species from Se-methylselenocysteine via the ylselenol (1, 7). We have used a chemically induced mammary tumor ␤-lyase enzyme. In contrast, methylseleninic acid already serves as a model in rats to evaluate the anticarcinogenic activity of Se-methyl- preformed active monomethylated metabolite, and this could be an un- selenocysteine, selenite, and selenomethionine. All three compounds derlying reason why methylseleninic acid acts more rapidly and exerts a were added in the diet and administered to the animals under the same more powerful effect than Se-methylselenocysteine in vitro. Interestingly, protocol. Our results indicated that there was a reproducible hierarchy the distinction between these two compounds disappeared in vivo, where of efficacy in the order of Se-methylselenocysteine Ͼ selenite Ͼ sel- their cancer chemopreventive efficacies were found to be very similar to enomethionine. The dose required for 50% tumor inhibition was 2 each other [in both methylnitrosourea and dimethylbenz(a)anthracene rat ppm Se for Se-methylselenocysteine, 3 ppm Se for selenite, and 4–5 mammary tumor models]. The ␤-lyase enzyme is present in many tissues; ppm Se for selenomethionine (3, 6, 8–10). thus, animals have an ample capacity to metabolize Se-methylselenocys- ␤ teine systemically. Therefore, Se-methylselenocysteine would be expected As noted above, a -lyase-mediated reaction is needed to free the to behave like methylseleninic acid if ␤-lyase is no longer a limiting factor. monomethylated selenium species from Se-methylselenocysteine. To Taken together, the present in vitro and in vivo results provide strong show conclusively the significance of this selenium metabolite in evidence in support of our earlier hypothesis that a monomethylated chemoprevention, we have investigated a novel compound, methyl- selenium metabolite is important for cancer chemoprevention. Methylse- seleninic acid (CH3SeO2H). This is a simple but stable selenium- leninic acid could be an excellent tool, especially for molecular mechanism containing reagent with a single methyl group. It represents a stripped- studies in cell culture, and some of these attributes are discussed. down version of Se-methylselenocysteine without the amino acid moiety (hence, no need for ␤-lyase). In this paper, we report both the INTRODUCTION in vitro and in vivo effects of methylseleninic acid in comparison to that of Se-methylselenocysteine. The cell culture studies included Over the past decade, our collaborative group has been focusing experiments on cell accumulation, DNA integrity, and apoptosis. The part of our research effort on the identification of the active metabolite animal studies were designed to evaluate the efficacy of mammary that is critical in selenium chemoprevention of cancer. It has been well cancer chemoprevention, tissue selenium levels, and selenium bio- documented that methylation is a prominent feature of selenite and availability in maintaining selenoenzymes. selenomethionine metabolism (1). Both compounds are metabolized via different pathways to H2Se, which is then sequentially methylated to methylselenol (CH3SeH), dimethylselenide (CH3-Se-CH3), and ϩ MATERIALS AND METHODS trimethylselenonium ion [(CH3)3Se ]. At high levels of selenium intake, dimethylselenide is expired in breath, whereas trimethylsele- Selenium Compounds. L-Se-Methylselenocysteine was obtained from Se- nonium is excreted in urine (2). Toward the goal of understanding the lenium Technologies, Inc. (Lubbock, TX). Methylseleninic acid was synthe- significance of these methylated metabolites, our strategy was to sized by the following method. Dimethyl diselenide (Aldrich Chemical Co.) select synthetic precursor compounds that were capable of delivering was oxidized with 3% hydrogen peroxide at 65°C until the yellow color of the diselenide had disappeared (ϳ3 mol of peroxide/mol of diselenide). The solution was adjusted to pH 7 with KOH and then applied to a column of Received 11/2/99; accepted 4/4/00. Dowex 1 (chloride). After washing with water until a negative starch/iodide The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with test was obtained, methylseleninic acid was eluted with 0.01 N HCl. The main 18 U.S.C. Section 1734 solely to indicate this fact. starch/iodide-positive fractions were pooled, adjusted to pH 7 with KOH, and 1 This work was supported by National Cancer Institute Grant CA 45164 and Roswell quantified by total selenium analysis and by iodometric titration of the iodine Park Cancer Institute Core Grant CA 16056. formed upon oxidation of iodide by methylseleninic acid. TLC on cellulose in 2 To whom requests for reprints should be addressed, at Department of Experimental Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. butanol:acetic acid:water (5:2:3) showed a single starch/iodide-positive spot at ϭ Phone: (716) 845-8875; Fax: (716) 845-8100; E-mail: [email protected]. Rf 0.42. Reduction with excess borohydride gave a UV peak (252 nm; mM 2882 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2000 American Association for Cancer Research. ANTICANCER ACTIVITY OF METHYLSELENINIC ACID extinction coefficient, 6.35) corresponding in wavelength and intensity to that scored at least 200 cells/sample. Live and dead apoptotic cells were identified of aliphatic selenolates. by nuclear condensation of chromatin stained by acridine orange and ethidium Cell Culture. The two mouse mammary hyperplastic epithelial cell lines bromide, respectively. The quantification of apoptotic cells was calculated as used in this study, TM2H and TM12, were obtained from the laboratory of a percentage of the total number of cells counted. Daniel Medina (11). Cells were grown at 37°C in a humidified incubator Design of Mammary Cancer Prevention Experiment. Mammary cancer containing 5% CO2 in DMEM and F-12 medium (1:1 ratio) containing 2% prevention by Se-methylselenocysteine or methylseleninic acid was studied adult bovine serum (Gemini Bioproducts), 10 ␮g/ml insulin (Intergen), 5 ng/ml with the use of both the MNU3 and DMBA models. Pathogen-free female epidermal growth factor (Intergen), and 5 ␮g/ml gentamicin (Life Technolo- Sprague Dawley rats were purchased from Charles River Breeding Laborato- gies, Inc.). ries. They were fed the standard AIN-76A diet for 5 days to acclimatize them Analysis of Cell Number Accumulation. The assay, which provides an to the powder ration. The AIN-76 mineral mix provides 0.1 ppm Se (as sodium estimate of the net effect on cell proliferation and cell death, used crystal violet selenite) to the diet. Rats were given a single dose of 10 mg of MNU i.p. or 10 staining of adherent cells as an end point (12). Briefly, cells (1000 cells/well) mg of DMBA intragastrically at 50 days of age. Each selenium compound was were seeded in flat-bottomed 96-well plates in 100 ␮l of culture medium. added to the basal
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