caa a22 4500 605507392 CHVBK 20210128100632.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00775-015-1254-6 doi (NATIONALLICENCE)springer-10.1007/s00775-015-1254-6 Thiol-mediated multiple mechanisms centered on selenodiglutathione determine selenium cytotoxicity against MCF-7 cancer cells [Elektronische Daten] [Takao Tobe, Koji Ueda, Motozumi Ando, Yoshinori Okamoto, Nakao Kojima] Selenium (Se) is an essential antioxidative micronutrient but can exert cancer-selective cytotoxicity if the nutritional levels are too high. Selenodiglutathione (GSSeSG) is a primary Se metabolite conjugated with two glutathione (GSH) moieties. GSSeSG has been suggested to be an important molecule for cytotoxicity. Here, we propose the underlying mechanisms for the potent cytotoxicity of GSSeSG: cellular intake; reductive metabolism; production of reactive oxygen species; oxidative damage to DNA; apoptosis induction. GSSeSG rather than selenite decreased cell viability and induced apoptosis accompanied by increases in intracellular Se contents. Therefore, GSSeSG-specific cytotoxicity may be ascribed to its preferable incorporation. Base oxidation and strand fragmentation in genomic DNA preceded cell death, suggesting that oxidative stress (including DNA damage) is crucial for GSSeSG cytotoxicity. Strand breaks of purified DNA were caused by the coexistence of GSSeSG and thiols (GSH, cysteine, homocysteine), but not the oxidized form or non-thiol reductants. This implies the important role of intracellular thiols in the mechanism of Se toxicity. GSH-assisted DNA strand breaks were inhibited by specific scavengers for hydrogen peroxide or hydroxyl radicals. The GSSeSG metabolite selenide induced some DNA strand breaks without GSH, whereas elemental Se did so only with GSH. These observations suggest involvement of Fenton-type reaction in the absence of transition metals and reactivation of inert elemental Se. Overall, our results suggest that chemical interactions between Se and the sulfur of thiols are crucial for the toxicity mechanisms of Se. SBIC, 2015 Selenodiglutathione nationallicence Cancer chemotherapy nationallicence Glutathione nationallicence Thiol nationallicence Sulfur nationallicence GSH : Glutathione nationallicence GSSeSG : Selenodiglutathione nationallicence GSSG : Oxidized glutathione nationallicence HSe− : Hydrogen selenide nationallicence H2SeO3 : Selenous acid nationallicence ROS : Reactive oxygen species nationallicence SSB : Single-strand break nationallicence Tobe Takao Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut Ueda Koji Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut Ando Motozumi Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, 650-8586, Kobe, Japan aut Okamoto Yoshinori Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut Kojima Nakao Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 687-694 0949-8257 20:4<687 2015 20 775 https://doi.org/10.1007/s00775-015-1254-6 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-015-1254-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tobe Takao Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut NATIONALLICENCE 700 1- Ueda Koji Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut NATIONALLICENCE 700 1- Ando Motozumi Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, 650-8586, Kobe, Japan aut NATIONALLICENCE 700 1- Okamoto Yoshinori Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut NATIONALLICENCE 700 1- Kojima Nakao Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Japan aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 687-694 0949-8257 20:4<687 2015 20 775