Iron nitroprusside as a chemodynamic agent and inducer of ferroptosis for ovarian cancer therapy

Abstract

ChemoDynamic Therapy (CDT) is a powerful therapeutic modality using Fenton/Fenton-like reactions to produce oxidative stress for cancer treatment. However, the insufficient amount of catalyst ions and ROS scavenging activity of glutathione peroxidase (GPX4) limit the application of this approach. Therefore, a tailored strategy to regulate the Fenton reaction more efficiently (utilizing dual metal cations) and inhibit the GPX4 activity, is in great demand. Herein, a CDT system is based on dual (Fe²⁺ metals) iron pentacyanonitrosylferrate or iron nitroprusside (FeNP) having efficient ability to catalyze the reaction of endogenous H₂O₂ to form highly toxic ˙OH species in cells. Additionally, FeNP is involved in ferroptosis via GPX4 inhibition. In particular, FeNP was structurally characterized, and it is noted that a minimum dose of FeNP is required to kill cancer cells while a comparable dose shows negligible toxicity on normal cells. Detailed in vitro studies confirmed that FeNP participates in sustaining apoptosis, as determined using the annexin V marker. Cellular uptake results showed that in a short time period, FeNP enters lysosomes and, due to the acidic lysosomal pH, releases Fe²⁺ ions, which are involved in ROS generation (˙OH species). Western blot analyses confirmed the suppression of GPX4 activity over time. Importantly, FeNP has a therapeutic effect on ovarian cancer organoids derived from High-Grade Serous Ovarian Cancer (HGSOC). Furthermore, FeNP showed biocompatible nature towards normal mouse liver organoids and in vivo. This work presents the effective therapeutic application of FeNP as an efficient Fenton agent along with ferroptosis inducer activity to improve CDT, through disturbing redox homeostasis.