Redox-Regulated Mechanisms of Cytotoxic Effect of Iron Nitrosyl Complex - Activator of Transcription Factor Nrf2 in Glioblastoma Cells In Vitro.

We performed a comprehensive in vitro study of a potential antiglioma compound from the class of NO donors, a nitrosyl iron complex with N-ethylthiourea (ETM), as an activator of redox-regulated mechanisms of cellular response. The effect of ETM on glioblastoma cells is accompanied by enhanced ROS generation, accumulation of intracellular NO, a decrease in mitochondrial membrane potential, and induction of caspase-3-dependent apoptosis. The studied complex acts as an activator of Nrf2 transcription factor, and the Nrf2/HO-1-dependent pathway plays a major role in regulating redox processes triggered by this complex. Induction of this pathway does not necessarily suppress the expression of NF-κB and its target genes, but prevents activation of NF-κB-mediated mechanisms of tumor cell protection. Nrf2 activation by ETM inhibits ferroptosis in glioblastoma cells, yet does not prevent apoptotic cell death. It can be assumed that the scenario of glioblastoma cell death under the effect of Nrf2 activators is largely determined by the ability of cells to quickly reconfigure the antioxidant system under conditions of oxidative stress.