Inhibition of reductase systems by 2-AAPA modulates peroxiredoxin oxidation and mitochondrial function in A172 glioblastoma cells
| Autor: | Andreza Fabro de Bem, Luiz Felipe de Souza, Alcir Luiz Dafre, Ariana Ern Schmitz, Carla I. Tasca, Marcelo Farina, Karen Andrinéia de Oliveira, Cláudia Beatriz Nedel, Luana Caroline da Silva |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Thioredoxin-Disulfide Reductase Cell Survival Thioredoxin reductase Glutathione reductase Antineoplastic Agents Biology Reductase Toxicology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Thiocarbamates Cell Line Tumor Glutaredoxin Humans Hydrogen Peroxide Peroxiredoxins General Medicine Glutathione Acetylcysteine Mitochondria Glutathione Reductase 030104 developmental biology chemistry Biochemistry Cumene hydroperoxide 030220 oncology & carcinogenesis Thioredoxin Glioblastoma Peroxiredoxin |
| Zdroj: | Toxicology in Vitro. 42:273-280 |
| ISSN: | 0887-2333 |
| DOI: | 10.1016/j.tiv.2017.04.028 |
| Popis: | Thiol homeostasis has a critical role in the maintenance of proper cellular functions and survival, being coordinated by the action of several reductive enzymes, including glutathione (GSH)/glutathione reductase (GR) and thioredoxin (Trx)/thioredoxin reductase (TrxR) systems. Here, we investigated the effects of the GR inhibitor 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) on the activity of thiol reductases (GR and TrxR), redox balance and mitochondrial function of A172 glioblastoma cells. 2-AAPA inhibited cell GR (IC50=6.7μM) and TrxR (IC50=8.7μM). A significant decrease in the cellular ability to decompose cumene hydroperoxide was observed and associated to a greater susceptibility to this peroxide. The redox state of peroxiredoxins (Prx1, Prx2 and Prx3) was markedly shifted to dimer 30min after treatment with 100μM 2-AAPA, an event preceding 2-AAPA-induced decrease in cell viability. Furthermore, mitochondrial function was also severely impaired, leading to a decrease in the respiratory control ratio, reserve capacity, and ATP synthesis-coupled respiration, as well as an increase in mitochondrial membrane potential. Our results indicate that inhibition of GR and TrxR activities, disruption of the ability to detoxify peroxides, increased oxidation of Prxs, as well as compromised mitochondrial function represent early events mediating 2-AAPA toxicity to A172 glioblastoma cells. |
| Databáze: | OpenAIRE |
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