Iron deprivation in cancer--potential therapeutic implications

Abstract

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation.

Figure 1

Intestinal absorption of iron. Ferric (Fe³⁺) iron present in the intestinal lumen is reduced to ferrous (Fe²⁺) iron, which can be transported by DMT1 across the apical surface of the enterocyte. Intracellular iron may be stored in ferritin, or transported out of the cell via ferroportin. After its release from the cell, it is oxidized by hephaestin and bound to transferrin for transport through the body.

Figure 2

Cellular iron metabolism. Iron laden transferrin is taken up by the cell via clathrin-mediated endocytosis of transferrin receptor-1 (TfR1). Acidification of the resultant endosome releases iron from TfR. Iron is transported out of the endosome via DMT1, and becomes part of the labile iron pool. Iron may then be used in a variety of cellular processes, stored as ferritin, or exported out of the cell via ferroportin.

Figure 3

Regulation of translation by intracellular iron through IRP binding to mRNA IREs. (A) mRNA is stabilized by the binding of the IRP to the 3′ IRE in the absence of iron. When iron is abundant, iron-bound IRP is displaced, allowing mRNA degradation. (B) Translation is repressed by the binding of an IRP to a 5′ IRE. Iron abundance removes the IRP and allows translation to proceed.

Figure 4

The chemical structure of several key iron chelators. Abbreviations: PIH––pyridoxal isonicotinoyl hydrazone; Dp44mT––di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone.