Intracellular Iron Concentration and Distribution Have Multiple Effects on Cell Cycle Events

Iron is essential for numerous cellular reactions that require oxygen transfer. Iron deficiency is a common problem in humans and is the most common nutritional disease worldwide. However, excess cellular iron can be toxic. Maintenance of iron hemostasis utilizes specialized pathways responsible for iron transport, iron uptake by cells, and appropriate cellular distribution of iron for utilization or storage. This chapter reviews how iron depletion is associated with inhibition of cellular proliferation and cell cycle arrest at different parts of the cell cycle. These effects are based on the effective chelation of iron, and more importantly on differences in various tissue responses to both iron depletion and iron toxicity. These differences may explain why in some tissues, particularly rapidly growing cancer cells, iron depletion causes cell cycle arrest and apoptosis, a form of programed cell death. Other neoplastic tissues are more prone to the toxic effects of iron, which can induce autophagic cell death (termed ferroptosis) via reactive oxygen species resulting in lysosomal degradation of cellular constituents. An appreciation of these differences can be utilized by novel pharmaceutical agents discussed below designed to treat specific cancers.