Numerous human diseases are linked to a biochemical condition known as oxidative stress (OS). Antioxidants are therefore becoming increasingly important as potential disease prevention and therapeutic agents. Since OS is a multi-stressor event, agents combining a range of different antioxidant properties, such as redox catalysis and metal binding, might be more effective and selective than mono-functional agents. Selenium derivatives of aniline and pyridine combine redox activity with metal binding properties. These multifunctional agents have a distinct electrochemical profile, and exhibit good catalytic activity in the glutathione peroxidase mimic and metallothionein assays. They also show antioxidant activity in a skin cell model of UVA-induced stress. These compounds might therefore provide the basis for novel agents combining two or more distinct antioxidant properties.

To examine the role of intracellular labile iron pool (LIP), ferritin (Ft), and antioxidant defence in cellular resistance to oxidative stress on chronic adaptation, a new H2O2-resistant Jurkat T cell line “HJ16” was developed by gradual adaptation of parental “J16” cells to high concentrations of H2O2. Compared to J16 cells, HJ16 cells exhibited much higher resistance to H2O2-induced oxidative damage and necrotic cell death (up to 3 mM) and had enhanced antioxidant defence in the form of significantly higher intracellular glutathione and mitochondrial ferritin (FtMt) levels as well as higher glutathione-peroxidase (GPx) activity. In contrast, the level of the Ft H-subunit (FtH) in the H2O2-adapted cell line was found to be 7-fold lower than in the parental J16 cell line. While H2O2 concentrations higher than 0.1 mM fully depleted the glutathione content of J16 cells, in HJ16 cells the same treatments decreased the cellular glutathione content to only half of the original value. In HJ16 cells, H2O2 concentrations higher than 0.1 mM increased the level of FtMt up to 4-fold of their control values but had no effect on the FtMt levels in J16 cells. Furthermore, while the basal cytosolic level of LIP was similar in both cell lines, H2O2 treatment substantially increased the cytosolic LIP levels in J16 but not in HJ16 cells. H2O2 treatment also substantially decreased the FtH levels in J16 cells (up to 70% of the control value). In contrast in HJ16 cells, FtH levels were not affected by H2O2 treatment. These results indicate that chronic adaptation of J16 cells to high concentrations of H2O2 has provoked a series of novel and specific cellular adaptive responses that contribute to higher resistance of HJ16 cells to oxidative damage and cell death. These include increased cellular antioxidant defence in the form of higher glutathione and FtMt levels, higher GPx activity, and lower FtH levels. Further adaptive responses include the significantly reduced cellular response to oxidant-mediated glutathione depletion, FtH modulation, and labile iron release and a significant increase in FtMt levels following H2O2 treatment.

Exposure of human skin cells to solar UVA radiation leads to an immediate dose-dependent increase of labile iron that subsequently promotes oxidative damage and necrotic cell death. Strong iron chelators have been shown to suppress cell damage and necrotic cell death by moderating the amount of labile iron pool (LIP), but chronic use would cause severe side effects owing to systemic iron depletion. Prodrugs that become activated in skin cells at physiologically relevant doses of UVA, such as "caged-iron chelators", may provide dose- and context-dependent release. Herein, we describe prototypical iron chelator compounds derived from salicylaldehyde isonicotinoyl hydrazone and pyridoxal isonicotinoyl hydrazone and demonstrate that the intracellular LIP and subsequent necrotic cell death of human skin fibroblasts is significantly decreased upon exposure to a combination of the prototypical compounds and physiologically relevant UVA doses. Iron regulatory protein bandshift and calcein fluorescence assays reveal decreased intracellular LIP following irradiation of caged-chelator-treated cells, but not in control samples where either UVA light, or caged-chelator is absent. Furthermore, flow cytometry shows that these compounds have no significant toxicity in the skin fibroblasts. This novel light-activated prodrug strategy may therefore be used to protect skin cells against the deleterious effects of sunlight.