Mitochondrially targeted deferasirox kills cancer cells via simultaneous iron deprivation and ferroptosis induction.

In principle, two separate ways to target cancer cells exist, the first one using iron deprivation and subsequent dysfunction of iron-dependent enzymes, and the second one inducing iron overload that leads to cell death known as ferroptosis. In this study, we introduce a compound that uniquely employs both pathways at once - mitochondrially targeted deferasirox (mitoDFX). MitoDFX deprives cells of biologically active iron while simultaneously depleting the primary cellular antioxidant glutathione (GSH) and inducing lipid peroxidation, both of which are hallmarks of ferroptosis. The role of the GSH is further supported by enhanced cell death in glutathione peroxidase 4 KO cells (GPX4 KO) induced by mitoDFX. This response is further exacerbated by simultaneous inhibition of glutathione metabolism or the pentose phosphate pathway. MitoDFX strongly affects the structure and function of mitochondria, leading to its fragmentation, ROS production and induction of mitophagy. Moreover, we found that mitoDFX treatment markedly reduces mitochondrial translation and downregulates levels of enzymatic subunits coupled with the ETC/TCA cycle as well as DNA replication and transcription, which could explain its strong cytostatic effects. In summary, mitoDFX achieves high activity and selectivity against cancer cells that seems unattainable for the conventional untargeted iron chelators, which have adverse effects on systemic iron metabolism. Our novel, targeted chelator has also shown enhanced efficacy in animal models, surpassing other mitochondrially targeted drugs and making mitoDFX a promising candidate for the development of future selective and highly effective cancer therapies.