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The Toxicity of a New Monophenolic Synthetic Inducer of Keap1/Nrf2/ARE Redox-Sensitive Signaling System In Vitro and In Vivo

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Abstract

Development of “indirect antioxidants” capable of activating redox-sensitive signaling systems, primarily the Keap1/Nrf2/ARE system, is a promising area of modern pharmacology. Among its chemical inducers is the hydrophilic monosubstituted monophenol sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate (TS-13) that we have developed. The aim of this study was to investigate the antiproliferative activity of TS-13 against BT-474 tumor cells in vitro and acute oral toxicity in mice in vivo. The relationship between TS-13 concentration and the proliferative activity of BT-474 human breast ductal carcinoma cells was determined by the MTT test with calculation of IC50. The results were compared with the previously obtained data for the MCF-7 line and compared with the functional properties of cells based on the level of gene expression (in silico GSEA analysis). Acute toxicity in vivo was examined on 50 C57Bl/6y female mice, which had a solution of TS-13 in distilled water administered to them at various doses via an intragastric tube. LD50 obtained experimentally was compared with predicted in silico using the GUSAR web service. The IC50 value of TS-13 for BT-474 cells calculated from the equation of exponential approximation was 59.5 μM, which was 2.2 times less than previously obtained for MCF-7 cells. This may be due to functional differences between BT-474 and MCF-7 cells, as evidenced by the results of GSEA analysis. The LD50 value established in the experiments in vivo was 936 mg/kg body weight of mice. The obtained value satisfactorily corresponds to the predicted in silico (561 mg/kg), although in reality the compound turned out to be somewhat less toxic than could be expected based on its structure. The study of the acute toxicity of the new water-soluble monophenol TS-13 allows it to be assigned to hazard class 4 on the Hodge–Sterner scale (low-toxicity compounds) or to hazard class 3 according to GOST (State Standard) 12.1.007-76 (moderately hazardous substances).

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ACKNOWLEDGMENTS

The work was performed using the equipment of the Center for Collective Use “Modern Optical Systems” and “Proteomic Analysis”, supported by funding from the Russian Ministry of Education and Science (Agreement no. 075-15-2021-691).

Funding

This work was carried out at the expense of the budget of the Federal Research Center of Fundamental and Translational Medicine, Novosibirsk.

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Authors and Affiliations

  1. Federal Research Center of Fundamental and Translational Medicine, 630117, Novosibirsk, Russia

    M. V. Khrapova, S. E. Khrapov, A. V. Chechushkov, P. M. Kozhin, L. P. Romakh, A. E. Serykh & E. B. Menshchikova

  2. Novosibirsk State Pedagogical University, 630126, Novosibirsk, Russia

    S. V. Kholshin & N. V. Kandalintseva

Authors
  1. M. V. Khrapova
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  2. S. E. Khrapov
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  3. A. V. Chechushkov
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  4. P. M. Kozhin
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  5. L. P. Romakh
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  6. A. E. Serykh
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  7. S. V. Kholshin
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  8. N. V. Kandalintseva
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  9. E. B. Menshchikova
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Correspondence to E. B. Menshchikova.

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Conflict of interest. The authors declare that they have no conflicts of interest.

Statement on the welfare of animals. In experiments with animals, the authors were guided by the rules adopted by the European Convention for the Protection of Animals used for Scientific Purposes (Strasbourg, 1986).

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Translated by I. Fridlyanskaya

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Khrapova, M.V., Khrapov, S.E., Chechushkov, A.V. et al. The Toxicity of a New Monophenolic Synthetic Inducer of Keap1/Nrf2/ARE Redox-Sensitive Signaling System In Vitro and In Vivo. Cell Tiss. Biol. 17, 299–305 (2023). https://doi.org/10.1134/S1990519X23030069

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  • DOI: https://doi.org/10.1134/S1990519X23030069

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