Toxicity of new monophenolic synthetic activator of Keap1/Nrf2/ARE redox-sensitive signaling system in vitro and in vivo

• Published in: Sibirskiĭ nauchnyĭ medit︠s︡inskiĭ zhurnal Vol. 42; no. 5; pp. 11 - 18
• Main Authors: Khrapova, M. V., Khrapov, S. E., Chechushkov, A. V., Kozhin, P. M., Romakh, L. P., Serykh, A. E., Kholshin, S. V., Kandalintseva, N. V., Menshchikova, E. B.
• Format: Journal Article
• Language: English; Russian
• Published: Russian Academy of Sciences, Siberian Branch Publishing House 27.10.2022
• Subjects: acute toxicity, proliferative activity, ld50, ic50, ts-13, mice, bt-474 line, keap1/nrf2/are signaling system
• ISSN: 2410-2512; 2410-2520
• DOI: 10.18699/SSMJ20220502

One of the promising areas of modern pharmacology is the development of «indirect antioxidants» capable of activating redox-sensitive signaling systems, primarily the Keap1/Nrf2/ARE system. Among its chemical inductors is the hydrophilic monosubstituted monophenol (3’-tert-butyl-4’-hydroxyphenyl)sodium propylthiosulfonate (TS-13) in development. The aim of the study was to investigate TS-13 antiproliferative activity against tumor cell line BT-474 in vitro and acute oral toxicity in mice in vivo.  Material and methods . The relationship between TS-13 concentration and proliferative activity of human breast ductal carcinoma cell line BT-474 was determined using the MTT test, the IC 50 was calculated and compared to the previously obtained for MCF-7 line; results were correlated with the functional properties of cells based on gene expression (in silico GSEA). In vivo acute toxicity was studied in 50 female C57Bl/6J mice, who received a TS-13 solution in distilled water at various doses by intragastric gavage. LD 50 obtained experimentally and predicted in silico using the GUSAR web service were compared.  Results and discussion. TS-13 inhibited the proliferation of BT-474 cells in a concentration-dependent manner (exponential approximation, IC 50 = 59.5 μM) and was 2.2 times more toxic than for MCF-7 cells. This may be due to functional differences between the BT-474 and MCF-7 lines, as evidenced by the GSEA results. The LD 50 value established in the in vivo experiment was 936 mg/kg body weight, 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.  Conclusions. A study of the acute toxicity of the new water-soluble monophenol TC-13 allows the classification of it as slightly toxic (toxicity rating level 4) according to the Hodge – Sterner scale) or as moderately hazardous (hazard class 3) according to GOST 12.1.007-76.