Transferrin Receptor-Driven Uptake of Fluorinated Chlorido Iron(III) Schiff Base Complexes

Fluorinated chlorido[salophene]iron(III) complexes (salophene = N,N′-bis(salicylidene)-1,2-phenylenediamine) are emerging as potent anticancer agents. While apoptosis and necrosis have been established as mechanisms of action, the involvement of ferroptosis and the cellular uptake pathways remain unclear. This study investigates the biological effects of fluorinated chlorido[salophene]iron(III) complexes (C1–C4), bearing fluorine substituents at positions 3, 4, 5, and 6 of the salicylidene groups. We focussed on their interaction with the Transferrin receptor-1 (TfR-1), their impact on mitochondrial function, and on mechanisms of cell death.

The complexes showed significant cytotoxicity in ovarian (A2780, A2780cis), breast (MDA-MB-231), and leukemia (HL-60) cancer cell lines, while sparing non-malignant stromal cells (HS-5) at a 0.5 µM concentration, the IC₅₀ for most cancer cell lines. Mitochondrial impairment was evident, demonstrated by reduced mitochondrial membrane potential and activity. Beyond apoptosis and necroptosis, ferroptosis was identified as part of the mode of action. For the first time, these complexes were shown to downregulate TfR-1 expression, mimicking the effects of Ferristatin II, an iron transport inhibitor promoting TfR-1 degradation. Increased intracellular iron(II) levels, detected using FerroOrange staining, further supported their role in driving ferroptosis.

In conclusion, fluorinated chlorido[salophene]iron(III) complexes exhibit tumor-specific cytotoxicity through multifaceted mechanisms, presenting a promising therapeutic approach for various cancers.