The multifaceted mechanism of action of quinoline thiosemicarbazone based on disruption of iron homeostasis and selective IGF1R inhibition leading to oxidative stress induction

In the present study, we introduce thiosemicarbazone derivatives with high antiproliferative activity against glioblastoma cells and high selectivity against healthy cells. The cellular studies were performed on a 3D spheroid model, which more closely reflects the conditions of an actual tumor. The tested thiosemicarbazone derivatives form complexes with iron ions, triggering the generation of reactive oxygen species, leading to cell death. The multitarget mechanism of action manifests through inhibition of the insulin receptor and the impact on iron metabolism and the disruption in redox homeostasis inducing oxidative stress in the cell. An additional advantage of the tested thiosemicarbazone derivatives is their ability to pass through the blood-brain barrier, which is crucial in the case of brain tumors. The effectiveness of the therapy was confirmed in a fish in vivo model, in which a reduction in tumor size in xerographs was recorded while maintaining minimal toxicity on a Zebrafish model. These results render the studied compounds attractive as potential drugs for therapy against glioblastoma.