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

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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 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.

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Abbreviations

GSH:

Glutathione

GSSeSG:

Selenodiglutathione

GSSG:

Oxidized glutathione

HSe− :

Hydrogen selenide

H2SeO3 :

Selenous acid

ROS:

Reactive oxygen species

SSB:

Single-strand break

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Acknowledgments

We are indebted to Dr. Kazuo Itoh and Dr. Yoshitaka Odo for the use of the ICP-MS. We would like to express gratitude to all the laboratory members who participated in this study for their technical support, especially Ms. Mai Takagi, Mr. Masayuki Hayashi, and Ms. Shino Matsuda for the data used in the present study. This work was supported by a Grant-in-Aid for Young Scientists (B) (Grant Number 23790161) and the Research Institute of Meijo University to K. U.

Conflict of interest

The authors declare they have no conflicts of interest.

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Authors and Affiliations

  1. Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan

    Takao Tobe, Koji Ueda, Yoshinori Okamoto & Nakao Kojima

  2. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan

    Motozumi Ando

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  1. Takao Tobe
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  2. Koji Ueda
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  4. Yoshinori Okamoto
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Correspondence to Nakao Kojima.

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Tobe, T., Ueda, K., Ando, M. et al. Thiol-mediated multiple mechanisms centered on selenodiglutathione determine selenium cytotoxicity against MCF-7 cancer cells. J Biol Inorg Chem 20, 687–694 (2015). https://doi.org/10.1007/s00775-015-1254-6

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  • DOI: https://doi.org/10.1007/s00775-015-1254-6

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