Thiol-mediated multiple mechanisms centered on selenodiglutathione determine selenium cytotoxicity against MCF-7 cancer cells

Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry
Takao TobeNakao Kojima

Abstract

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 p...Continue Reading

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Citations

Oct 31, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maja KozarskiLeo van Griensven
Jul 19, 2015·Cancer Letters·Lingying TongLi Zuo
Jan 11, 2017·The Journal of Toxicological Sciences·Takao TobeHideto Jinno
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Jul 4, 2021·European Journal of Medicinal Chemistry·Hongyan ChuaiMinhang Xin
Aug 3, 2021·Antimicrobial Agents and Chemotherapy·Mikel Etxebeste-MitxeltorenaCarmen Sanmartín

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