engleski

Chemosensitivity of human neuroblastoma cells to different oximes

The aim of this study was to establish the chemosensitivity pattern of human neuroblastoma cells (SH-SY5Y) to novel pyridinium and imidazolium oximes currently tested as antidotes in organophosphorus compound (OPs) poisoning. OPs are highly toxic inhibitors of synaptic acetylcholinesterases (AChE, EC 3.1.1.7) in the central and peripheral nervous systems, and exposure to even a small dose of these compounds has severe consequences for the organism. Oximes act as reactivators of AChE inhibited by an OP and restore vital functions. Therefore, neurons present the primary site of action of such oximes. In the search for more efficient antidotes, a new approach has begun to take shape concerning oxime design. Lipophilic moieties were introduced to the oxime core molecule to enhance penetration through the blood brain barrier ; also the presence of oxime’s tertiary amine was omitted. In this study, we selected such charged and uncharged lipophilic oximes that showed promising properties in in vitro reactivation, and tested their effects on SH-SY5Y cells. The oximes were tested at concentrations of up to 0.8 mM and their effect was compared to the effect of pyridinium oximes HI-6 and 2PAM currently used in medicinal practice. As our results indicate, cell response to the oximes varied greatly with their structure. Cells seemed to be more sensitive to the uncharged oximes carrying several aromatic moieties than to the charged ones with the presence of the quaternary nitrogen. However, several newly developed oximes provoked in vitro cytotoxic effect and influenced the viability of treated cells in concentrations relevant for reactivation studies (IC50 ≤ 300 μM). Though the exact mechanism of observed chemosensitivity of human neurblastoma cells to these oximes needs to be elucidated, such an unwanted effect on cells presents a major drawback limiting their further development as potential pharmaceuticals. Moreover, the currently used charged pyridinium oximes HI-6 and 2PAM did not induce chemosensitivity in the studied concentration range.Acknowledgment: This work was supported by the Croatian Science Foundation grant no. 4307

SH-SY5Y cells ; oximes ; cytotoxic effect

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