Targeting iron metabolism in cancer therapy

Abstract

Iron is a critical component of many cellular functions including DNA replication and repair, and it is essential for cell vitality. As an essential element, iron is critical for maintaining human health. However, excess iron can be highly toxic, resulting in oxidative DNA damage. Many studies have observed significant associations between iron and cancer, and the association appears to be more than just coincidental. The chief characteristic of cancers, hyper-proliferation, makes them even more dependent on iron than normal cells. Cancer therapeutics are becoming as diverse as the disease itself. Targeting iron metabolism in cancer cells is an emerging, formidable field of therapeutics. It is a strategy that is highly diverse with regard to specific targets and the various ways to reach them. This review will discuss the importance of iron metabolism in cancer and highlight the ways in which it is being explored as the medicine of tomorrow.

Keywords: Cancer; Chelation; Ferroptosis; Iron metabolism; Therapy.

Figure 1

Iron absorption and recycling. Non-heme iron is absorbed into enterocytes by DMT-1 after reduction from Fe (III) to Fe(II) by DcytB. Iron is carried by chaperones such as PCBPs to sites for storage in ferritin or for functional usage in cellular proteins and metabolism. Iron can be exported through FPN and subsequently re-oxidized by HEPH to Fe (III). Most circulating iron is carried by Tf and delivered to various tissues via its receptor TfR1 through receptor-mediated endocytosis. Tf and ferric iron dissociate in the endosome, after which the ferric iron is reduced to ferrous iron by STEAP proteins and enters the cytosol. Circulating iron is mainly derived from phagocytosis in senescent red blood cells, a process mediated by macrophages. Iron loss from the body occurs regularly through tissue loss such as epithelial shedding and blood loss. DMT-1: divalent metal transporter 1; DcytB: duodenal cytochrome B; PCBP: poly(rC)-binding protein; FPN: ferroportin; HEPH: hephaestin; STEAP: six transmembrane epithelial antigen of the prostate; Tf: transferrin; TfR1: transferrin receptor 1. Created with BioRender.com

Figure 2

Major regulators of iron homeostasis include hepcidin, HIFs and IRP/IRE systems. [A] Hepcidin naturally limits the amount of iron efflux from cells and is inhibited by conditions such as anemia, hypoxia, increased testosterone, and increased erythropoiesis, while being upregulated by systemic iron overload and inflammation. [B] HIFs respond to low oxygen and iron levels and transcribe genes to help cells adapt to perceived environmental deficiencies for a more sustainable metabolism and long-term survival; this results in short- and long-term changes including increases in glycolysis, angiogenesis, iron supplies, and ultimately cell vitality. [C] IRPs control gene translation through binding of IREs on mRNA transcripts for iron metabolism-related proteins, either promoting translation through 3' UTR binding-dependent stabilization (e.g., TfR1, DMT1), or inhibiting translation through 5' UTR binding that results in eventual degradation (e.g., Ferritin, FPN). HIF: hypoxia-inducible factor; IRP: iron response protein; IRE: iron response element; mRNA: messenger RNA; UTR: untranslated region. Created with BioRender.com

Figure 3

Potential therapeutic pathways in cancer targeting abnormal iron metabolism. [A] Iron chelators limit the available amount of iron in tumor cells. Chelators and other drugs can be delivered through a TfR1-mediated drug delivery. [B] Inhibiting TfR1 by antibodies and gene silencing can lower iron import, depriving the cell of its desired iron content. [C] Inhibition of HIFs and their target genes can ultimately limit the amount of iron available for cells and hinder the ability of cancer cells to proliferate. [D] Inhibition of hepcidin-FPN axis can increase cellular iron export depriving the cell of iron. [E] Inhibition of cellular antioxidant defenses such as system xC- and GPX4 renders the cell prone to ROS accumulation from iron metabolism, leading to lipid peroxidation and ferroptosis. TfR1: transferrin receptor; HIFs: hypoxia-inducible factors; FPN: ferroportin; xC-: cystine-glutamate antiporter; GPX4: glutathione peroxidase 4; ROS: reactive oxygen species. Created with BioRender.com