Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs
Section snippets
PIH analogs and their Fe3+ complexes
PIH analogs were synthesized by the condensation of the corresponding aldehydes and hydrazides as described [16]. Fe complexes were formed by the addition of FeCl3 (Fisher, Fair Lawn, NJ), dissolved in sodium citrate, and chelator, dissolved in NaOH, in a 1:2 molar ratio, and incubation at room temperature for 1 h following neutralization [10].
Toxicity
Jurkat T lymphocytes and K562 cells were cultured in phenol-red-free RPMI-1640 (Cellgro, Herndon, VA) supplemented with 10% FBS and 2 mM glutamine (Gibco,
Toxicity of PIH analogs and their Fe3+ complexes; effect of GSH depletion
The toxicity of PIH analogs, the structures of which are shown in Fig. 1, and their Fe3+ complexes toward Jurkat T lymphocytes was determined after 72 h incubation (Table 1). The structure–activity relationships describing the toxicity of PIH analogs in Jurkat cells were similar to those in K562 cells [10] and SK-N-MC cells [22], suggesting a common mechanism of action of these iron chelators among different cell types. Toxicity increased with the lipophilicity of the analogs, as has been
Redox cycling by Fe complexes of PIH analogs
K562 cells reduce the Fe complexes of PIH analogs (Table 3), as does the ubiquitous cellular reductant, ascorbate. In contrast, cyclic voltammetry of Fe(SBH)2[33] and Fe(NIH)2[34] demonstrated the absence of a reversible redox potential in the biologically accessible range; from these data, it was concluded that reduction of these complexes by cells is not possible. It may be, however, that these experiments were confounded by the relatively slow kinetics of ligand exchange characteristic of
Acknowledgements
This work was supported by grants from the Canadian Institutes for Health Research (P.P.) and University of Linkoping Grant #83081030 (J.N.), and postdoctoral fellowships from the National Cooley’s Anemia Foundation and the Thalassemia Foundation of Canada (J.L.B.).
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Present address: Heart Foundation Research Center, School of Health Sciences, Griffith University, Southport, Queensland, Australia.