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Anti-cancer therapy by iron chelation has been shown to inhibit many cellular processes including DNA replication, mitochondrial metabolism and oncogenic signalling pathways (e.g., EGFR). Iron chelator SK4 represents a double pronged approach towards treating cancer. SK4 enters through LAT1, a commonly overexpressed amino acid transporter in tumours, thus targeting iron addiction and LAT1 overexpression. The aim of this study was to characterise the mode of action of SK4 through proteomics, metabolomics, lipidomics and seahorse real-time analysis in ovarian cell line SKOV3 and triple negative breast cancer cell line MDA MB 231. Pathway enrichment of proteomics data showed an overrepresentation of metabolism related pathways. Metabolic change after SK4 exposure have been confirmed in investigations of changes in basal and maximal mitochondrial respiration using seahorse real-time analysis of mitochondrial metabolism. Metabolomics also showed an increase in AMP and glucose-1-phosphate. Interestingly, our lipidomics data show a decrease in phospholipid synthesis in the SKOV3 cells which is in contrast with previous data which showed an upregulation of ceramide driven apoptosis. In summary, our data highlight impairment of energy metabolism as a mechanism of action underlying SK4 apoptosis, but also suggest a potential role of ceramide induction in the phenotypic outcome of the cell model.

Iron is a key metal involved in several biological processes such as DNA replication and repair, cellular proliferation and cell cycle regulation. Excess volumes of labile iron are toxic and can lead to the production of ROS (reactive oxygen species) via Fenton chemistry. Due to this reactive nature, it can contribute to DNA damage and genomic instability. Therefore, excess iron in the labile iron pool is associated with cancer, which has made the labile iron pool a crucial target for anticancer therapy by targeting iron. This iron can be incorporated into essential enzymes such as ribonucleotide reductase (RnR). Over several decades of research, iron chelators function as more than just RnR inhibitors. Indeed, a plethora of iron chelator mechanisms can result in therapeutic properties that can target critical steps of cancer cells’ aberrant biological abilities such as proliferation, migration and metastasis. One such mechanism is the production of redox-active complexes that can produce toxic levels of ROS in cancer cells. Cancer cells are potentially more susceptible to ROS production or modulation of antioxidant levels. Understanding iron metabolism is vital in targeting cancer. For instance, Fe-S clusters have recently been shown to play crucial roles in cell signalling by ROS through their incorporation into essential DNA replication and repair enzymes. ROS can also degrade Fe-S clusters. Iron chelators that produce toxic levels of ROS, therefore, could also target Fe-S centres. Thus, the design of iron chelators is important, as this can determine if it will participate in redox cycling and produce ROS or if it is solely used to remove iron. This review focuses on alterations in cancer iron metabolism, iron’s role in genomic stability and how the design of chelators can use Fenton chemistry to their advantage to cause DNA damage in cancer cells and potentially inhibit Fe-S centres.