Effects of Ferrocene and Ferrocenium on MCF-7 Breast Cancer Cells and Interconnection with Regulated Cell Death Pathways.

The effects of ferrocene ( Fc ) and ferrocenium ( Fc + ) induced in triple negative human breast cancer MCF-7 cells were explored by immunofluorescence, flow cytometry, and transmission electron microscopy analysis. The different abilities of Fc and Fc + to produce reactive oxygen species and induce oxidative stress were clearly observed by activating apoptosis and morphological changes after treatment, but also after tests performed on the model organism D. discoideum , particularly in the case of Fc + . The induction of ferroptosis, an iron-dependent form of regulated cell death driven by an overload of lipid peroxides in cellular membranes, occurred after 2 h of treatment with Fc + but not Fc . However, the more stable Fc showed its effects by activating necroptosis after a longer-lasting treatment. The differences observed in terms of cell death mechanisms and timing may be due to rapid interconversion between the two oxidative forms of internalized iron species (from Fe 2+ to Fe 3+ and vice versa). Potential limitations include the fact that iron metabolism and mitophagy have not been investigated. However, the ability of both Fc and Fc + to trigger different and interregulated types of cell death makes them suitable to potentially overcome the shortcomings of traditional apoptosis-mediated anticancer therapies.