Cytotoxicity and enhancement of the insulin signaling pathway induced by peroxidovanadium(V) complexes

Vanadium compounds are known to possess a variety of physiological actions, including insulin-mimetic activities. We synthesized two peroxidovanadium(V) complexes (pVs) having the amino acid derivative N-(4-imidazolylmethyl)-l-alanate (imala) or N-(4-imidazolylmethyl)-l-phenylalanate (imphe) as an ancillary ligand. The pVs stimulated the proliferation of H4IIEC3 rat hepatoma cells at low doses while they resulted in cytotoxicity at high concentrations. Their insulin-mimetic activities were comparable to vanadium complexes. The signal transduction pathways induced by these compounds were examined in an effort to understand their suitability for therapeutic applications. When the cells were treated with the pVs, reactive oxygen species (ROS) were generated, and increased in a dose-dependent manner. In addition, the activation of cellular stress signals was also enhanced in a dose-dependent manner. It was found that ROS generated by the treatment with pVs at a high dose act as a stress inducer for the cells.