engleski

Triggering apoptosis in human cells by 3-hydroxy-2- pyridine oximes

Pyridinium core-based oximes are primarily investigated as reactivators of synaptic acetylcholinesterase inhibited by organophosphorus nerve agents and pesticides. In the search for efficient antidotes, numerous structures have been synthesised, but for many of them side-effects and cytotoxicity are observed in their early-stage testing. Therefore, we aimed to investigate what causes this cytotoxicity for one of the oxime series, and whether it could be related to small differences in structural motives. We tested the effect of five 3-hydroxy-2-pyridine oximes on the viability of neuroblastoma SH-SY5Y cells, representing nerves as the main target of oxime antidotes action. The cytotoxic effect was monitored in a time- and dose-dependent manner. The results indicated apoptosis induction via the mitochondrial-dependent pathway by caspase 9 and/or 3 activation, accompanied by DNA damage, increased phosphorylation of MAPK kinase or acetyl-CoA carboxylase (ACC) and decreased phosphorylation of the transcription factor STAT3. We assume that 3-hydroxy-2-pyridine oximes target mitochondria and cellular metabolism of the fatty acids, due to increased phosphorylation of ACC. Furthermore, a hydroisoquinoline moiety in the structure seems to be responsible for triggering apoptosis, where dimethylamino-phenyl group had the most significant effect on cytotoxicity and activation of additional apoptosis initiator - caspase 8. In conclusion, even though these oximes cannot be considered as candidates in organophosphorus antidote research due to such influence on cells, they could be introduced in studies on other specific targets and as potential new drugs for different conditions. This work was supported by the Croatian Science Foundation (HrZZ-UIP-2017- 05-7260), Slovenian Research Agency (J3-9263 and J3-2523, P3-0043 and J7-8276) and Croatian-Slovenian Bilateral grant 2020-2021 (BI-HR/20-21-041).

cytotoxicity ; apoptotis ; caspase ; oximes

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