Clioquinol, a lipophilic Zn2+ chelator, augments and attenuates the cytotoxicity of H2O2: a bell-shaped response curve of the effects of the drug

Abstract

Clioquinol, a lipophilic Zn²⁺ chelator, has emerged as a potential novel therapeutic agent for several diseases such as cancer and Alzheimer's disease. Clioquinol has different effects on the intracellular Zn²⁺ concentrations in rat thymocytes, depending on its concentration and extracellular Zn²⁺ levels. In this study, we examined the effect of clioquinol on cells under oxidative stress induced by hydrogen peroxide (H₂O₂) by using a conventional flow cytometric technique with appropriate fluorescent probes. We observed a bell-shaped relationship between the clioquinol concentration and changes in H₂O₂ cytotoxicity; H₂O₂-induced cytotoxicity was the highest at a clioquinol concentration of 100 nM. Zn²⁺ chelators significantly decreased the clioquinol-induced increase in H₂O₂ cytotoxicity. A bell-shaped curve was observed between the increase in H₂O₂-induced cytotoxicity by clioquinol and the intracellular Zn²⁺ concentrations, although the maximal increases in Zn²⁺ levels were induced by 300 nM clioquinol. In addition, clioquinol at concentrations ≥100 nM exerted antioxidant activity by decreasing the cellular oxidant levels. Thus, clioquinol can exert pro-oxidant or antioxidant effects, depending on its concentration and the extracellular concentration of Zn²⁺. Because of the unique Zn²⁺-dependent effects and toxicological profile of clioquinol, clioquinol should be considered for clinical use.