Activation of (un)regulated cell death as a new perspective for oxime activity research (CROSBI ID 705068)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Zandona, Antonio ; Maraković, Nikola ; Miš, Katarina ; Dolinar, Klemen ; Pirkmajer, Sergej ; Katalinić, Maja
engleski
Activation of (un)regulated cell death as a new perspective for oxime activity research
Compounds known as oximes are tested as antidotes against the toxic effects of organophosphates (OP). Oximes have diverse scaffolds, created with the purpose to fit the active site of the acetylcholinesterase-OP conjugate as their main target in the organism. After primary screening, candidates which meet the in vitro kinetic parameters of action as antidotes are promoted to further evaluation, while others are discarded. Our previous research showed that some of the oximes display toxic effects on cell level which could be explored beyond their main mechanism of action. To investigate this further, we performed an in vitro cell-based evaluation of four structurally diverse groups of oximes at concentrations of up to 0.8 mM, identifying specific biomarkers. We tested the effect of oximes on several in vitro cell models: skeletal muscles, kidneys, liver, and neurons. As our results indicate, the effect of oximes was consistent in all cells tested. Compounds with quinuclidine and imidazolium core induced unregulated cell death caused by cell burst, with increased levels of reactive oxygen species formation, but without antioxidant scavenging activation. On the other hand, oximes with a pyridine or pyridinium core activated apoptosis and specific caspases-3, -8, and/or -9. Interestingly, some of the compounds even had a synergistic effect. We generated a pharmacophore model for each series and identified ligands from public databases that map to generated pharmacophores. Several interesting hits were obtained including well known chemotherapy agents, gene expression modulators, antibiotics, cytochrome P450 modulators, etc. Even though the exact mechanism by which oximes act to trigger observed cell effects needs to be explained, our findings should open up a whole new perspective for oxime research. Acknowledgement: This work was supported by the Croatian Science Foundation under the project UIP-2017-05-7260 and by Croatian-Slovenian bilateral grant 2020-2021
cytotoxicity ; apoptotis ; necrosis ; caspase ; pharmacophore
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Podaci o prilogu
364-364.
2021.
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objavljeno
10.1002/2211-5463.13205
Podaci o matičnoj publikaciji
FEBS Open Bio
Federation of European Biochemical Societies (FEBS)
2211-5463
Podaci o skupu
45th FEBS Congress: Molecules of Life: Towards New Horizons (FEBS 2021)
poster
03.07.2021-08.07.2021
Ljubljana, Slovenija