Biological response and cell death signaling pathways modulated by tetrahydroisoquinoline-based aldoximes in human cells - Normandie Université Accéder directement au contenu
Article Dans Une Revue Toxicology Année : 2023

Biological response and cell death signaling pathways modulated by tetrahydroisoquinoline-based aldoximes in human cells

Antonio Zandona
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Josip Madunić
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Katarina Miš
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Nikola Maraković
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Marco Cavaco
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Petra Mišetić
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Jasna Padovan
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Miguel Castanho
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Sergej Pirkmajer
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Vera Neves
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Maja Katalinić
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Résumé

The uncharged 3-hydroxy-2-pyridine aldoximes with protonatable tertiary amines are studied as antidotes in toxic organophosphates (OP) poisoning. Due to some specific structural features they have, we hypothesize that these compounds could exert diverse biological activity beyond their main scope of application. To examine this further, we performed an extensive cell-based assessment to determine their effects on human cells and possible mechanism of action. As our results indicated, in the concentration range up to 800 μM, aldoxime having piperidine moiety did not induce significant toxicity, while those with tetrahydroisoquinoline moiety stimulated mitochondria-mediated activation of the intrinsic apoptosis pathway through ERK1/2 and p38-MAPK signaling and subsequent activation of initiator caspase 9 and executive caspase 3 accompanied with DNA damage. Mitochondria and fatty acid metabolism were also likely targets of 3-hydroxy-2-pyridine aldoximes, due to increased phosphorylation of acetyl-CoA carboxylase. In silico analysis predicted kinases as their most probable target class, while pharmacophores modeling additionaly predicted the inhibition of a cytochrome P450cam, as well. Overall, observed biological activity of aldoximes with tetrahydroisoquinoline moiety could be indicative for future design of compounds either in a negative context in OP antidotes design, or in a positive one for design of compounds for the treatment of other conditions and diseases, such as cancer.
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hal-04635900 , version 1 (04-07-2024)

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Antonio Zandona, Josip Madunić, Katarina Miš, Nikola Maraković, Pierre Dubois-Geoffroy, et al.. Biological response and cell death signaling pathways modulated by tetrahydroisoquinoline-based aldoximes in human cells. Toxicology, 2023, 494, pp.153588. ⟨10.1016/j.tox.2023.153588⟩. ⟨hal-04635900⟩
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