Molecular mechanisms of iron uptake by cells and the use of iron chelators for the treatment of cancer.

The field of iron (Fe) metabolism has been invigorated in the past 10 years with the discovery of a variety of new molecules involved in the homeostatic control of this critical nutrient. These proteins include the transferrin receptor 2, frataxin, hephaestin, hepcidin, hemojuvelin and others. Basic understanding of the metabolism of Fe in cells is vital in order to develop Fe chelators for the treatment of a variety of disease states. In addition, examination of the role of Fe in the regulation of cell cycle progression and angiogenesis has led to investigations of the use of novel Fe chelators as anti-proliferative agents. These studies have resulted in the identification of new ligands that show selective and potent anti-tumor activity in vitro and in vivo. Moreover, the ability of these chelators to inhibit growth is not only limited to the inhibition of DNA synthesis. In fact, there is a range of targets that are affected by Fe-depletion, such as molecules involved in cell cycle control, angiogenesis and metastasis suppression. These include hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor-1 (VEGF1), p21(CIP1/WAF1), cyclin D1 and the protein product of the N-myc downstream regulated gene-1 (Ndrg1). As such, Fe chelators can now be designed to target molecules to induce specific effects, for instance, angiogenesis or metastasis suppression.