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The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells

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Abstract

The mesoionic compound 4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride (MI-D) impairs mitochondrial oxidative phosphorylation and has a significant antitumour effect against hepatocarcinoma and melanoma. This study evaluated the cytotoxic effect of MI-D on T98G glioblastoma cells and investigated whether the impairment of oxidative phosphorylation promoted by MI-D is relevant to its cytotoxic effect. The effects of MI-D on T98G cells cultured in high glucose Dulbecco’s modified Eagle’s medium (DMEM) HG (glycolysis-dependent) and galactose plus glutamine-supplemented Dulbecco’s modified Eagle’s medium (DMEM) GAL (oxidative phosphorylation-dependent) were compared. T98G cells grown in DMEM GAL medium exhibited higher respiration rates and citrate synthase activity and lower lactate levels, confirming the metabolic shift to oxidative phosphorylation in these cells. MI-D significantly decreased the cell viability in a dose-dependent manner in both media; however, T98G cells cultured in DMEM GAL medium were more susceptible. The mesoionic significantly inhibited mitochondrial oxidative phosphorylation of glioma cells in both media. At the same time, lactate levels were not altered, indicating an absence of compensatory glycolysis activation. Additionally, MI-D increased the citrate synthase activity of cells in both media, which in DMEM HG-cultivated cells was followed by citrate accumulation. Apoptosis dependent on caspase-3 mediated the toxicity of MI-D on T98G cells. The higher susceptibility of glioma cells cultured in DMEM GAL medium to MI-D indicates that the impairment of mitochondrial functions is involved in mesoionic cytotoxicity. The results of this study indicate the potential use of MI-D for glioblastoma treatment.

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Data availability

All data collected and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Luis Paulo Silveira Alves for helping with the flow cytometric analysis.

Funding

This study was supported by the Brazilian research funding agencies CNPq (Conselho Nacional para o Desenvolvimento Científico e Tecnológico) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). SMSCC also received grant support from CNPq (process 423759/2016-7). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Federal University of Parana, Curitiba, Brazil

    Marília Locatelli Corrêa-Ferreira, Amanda do Rocio Andrade Pires, Guilherme Henrique Pedrassoli, Sheila Maria Brochado Winnischofer, Guilhermina Rodrigues Noleto & Sílvia Maria Suter Correia Cadena

  2. Department of Chemistry, Federal Rural University of Rio de Janeiro, Rio de Janeiro, Brazil

    Igor Resendes Barbosa & Aurea Echevarria

  3. Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, Coronel Francisco H. Dos Santos, C. Postal 19046, Curitiba, Paraná, 81531-990, Brazil

    Sílvia Maria Suter Correia Cadena

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Contributions

MLCF: formal analysis, investigation, methodology, validation, writing, design of experiments. AdRAP: investigation, methodology, validation, design of experiments, conceptualization. IRB: investigation, review. AE: investigation, resources, review, conceptualization. GHP: investigation, review; SMBW: review, edition, resources, conceptualization. GRN: analysis of data, review, edition, resources, conceptualization. SMSCC: formal analysis, writing, review, edition, resources, conceptualization, supervision. All authors have approved the final manuscript and have agreed to be accountable for all the aspects of the work.

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Correspondence to Sílvia Maria Suter Correia Cadena.

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The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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The authors declare that this manuscript is original, has not been published before and is not currently being considered for publication. The study was performed using glioma T98G cells acquired from American Type Culture Collection - ATCC (Material and Methods section) and was approved by the local commission from the Graduate Program in Science - Biochemistry - Federal University of Paraná - Brazil.

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Corrêa-Ferreira, M.L., do Rocio Andrade Pires, A., Barbosa, I.R. et al. The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells. Mol Cell Biochem 477, 2033–2045 (2022). https://doi.org/10.1007/s11010-022-04423-2

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