Zinc at clinically-relevant concentrations potentiates the cytotoxicity of polysorbate 80, a non-ionic surfactant

Polysorbate 80, a non-ionic surfactant, is used in the formula of water-insoluble anticancer agents for intravenous application. In our recent studies, this surfactant decreased cellular thiol content and the chemicals decreasing cellular thiol content increased intracellular Zn2+ concentration. In this study using rat thymocytes, the effect of polysorbate 80 on FluoZin-3 fluorescence, an indicator for intracellular Zn2+, and the influence of ZnCl2 on cytotoxicity of polysorbate 80 were examined in order to test the possibility that Zn2+ is involved in cytotoxic action of polysorbate 80. The surfactant at concentrations of 10 μg/ml or more significantly augmented FluoZin-3 fluorescent in a concentration-dependent manner, indicating an increase in intracellular Zn2+ concentration. The increase by polysorbate 80 was also observed after removing extracellular Zn2+, suggesting an intracellular Zn2+ release. The simultaneous application of polysorbate 80 (30 μg/ml) and ZnCl2 (10–30 μM) significantly increased cell lethality. The simultaneous application of ZnCl2 accelerated the process of cell death induced by polysorbate 80 and the combination increased oxidative stress. Results may indicate that the cytotoxicity of polysorbate 80 at clinical concentrations is modified by micromolar zinc. Although there is no clinical report that polysorbate 80 and zinc salt are simultaneously applied to human as far as our knowledge, it may be speculated that zinc induces some diverse actions in cancer treatment with water-insoluble anticancer agent including nanoparticle drug of which the solvent is polysorbate 80.