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Dithiolethiones D3T and ACDT Protect Against Iron Overload-Induced Cytotoxicity and Serve as Ferroptosis Inhibitors in U-87 MG Cells

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Abstract

Iron overload-induced oxidative stress is implicated in various neurodegenerative disorders. Given the numerous adverse effects associated with current iron chelators, natural antioxidants are being explored as alternative therapeutic options. Dithiolethiones found in cruciferous vegetables have emerged as promising candidates against a wide range of toxicants owing to their lipophilic and cytoprotective properties. Here, we test the dithiolethiones 3H-1,2-dithiole-3-thione (D3T) and 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) against ferric ammonium citrate (FAC)-induced toxicity in U-87 MG astrocytoma cells. Exposure to 15 mM FAC for 24 h resulted in 54% cell death. A 24-h pretreatment with 50 μM D3T and ACDT prevented this cytotoxicity. Both dithiolethiones exhibited antioxidant effects by activating the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor and upregulating levels of intracellular glutathione (GSH). This resulted in the successful inhibition of FAC-induced reactive oxygen species, lipid peroxidation, and cell death. Additionally, D3T and ACDT upregulated expression of the Nrf2-mediated iron storage protein ferritin which consequently reduced the total labile iron pool. A 24-h pretreatment with D3T and ACDT also prevented cell death induced by the ferroptosis inducer erastin by upregulating the transmembrane cystine/glutamate antiporter (xCT) expression. The resulting increase in intracellular GSH and alleviation of lipid peroxidation was comparable to that caused by ferrostatin-1, a specific ferroptosis inhibitor. Collectively, our findings demonstrate that dithiolethiones may show promise as potential therapeutic options for the treatment of iron overload disorders.

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Acknowledgements

The authors would like to acknowledge Dr. Dennis Brown from Manchester University, College of Pharmacy, Natural & Health Sciences, Fort Wayne, IN, and Dr. Timothy J. Maher from Massachusetts College of Pharmacy and Health Sciences, School of Pharmacy, Boston for their scientific input.

Funding

This study was funded by Massachusetts College of Pharmacy and Health Sciences, School of Pharmacy, Boston, MA.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, MA, 02115, USA

    Neha Kulkarni, Rajitha Gadde & Swati Betharia

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NK: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing an initial draft, visualization. RG: validation, formal analysis, investigation, data curation, writing an initial draft. SB: conceptualization, methodology, data curation, writing- editing, critical review, and revision of the manuscript, supervision, project administration, funding acquisition.

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Kulkarni, N., Gadde, R. & Betharia, S. Dithiolethiones D3T and ACDT Protect Against Iron Overload-Induced Cytotoxicity and Serve as Ferroptosis Inhibitors in U-87 MG Cells. Neurochem Res 48, 2542–2551 (2023). https://doi.org/10.1007/s11064-023-03927-7

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