Cancer cells with irons in the fire

Abstract

Iron is essential for the growth and proliferation of cells, as well as for many biological processes that are important for the maintenance and survival of the human body. However, excess iron is associated with the development of cancer and other pathological conditions, due in part to the pro-oxidative nature of iron and its damaging effects on DNA. Current studies suggest that iron depletion may be beneficial for patients that have diseases associated with iron overload or other iron metabolism disorders that may increase the risk for cancer. On the other hand, studies suggest that cancer cells are more vulnerable to the effects of iron depletion and oxidative stress in comparison to normal cells. Therefore, cancer patients might benefit from treatments that alter both iron metabolism and oxidative stress. This review highlights the pro-oxidant effects of iron, the relationship between iron and cancer development, the vulnerabilities of the iron-dependent cancer phenotype, and how these characteristics may be exploited to prevent or treat cancer.

Keywords: Cancer; Free radicals; Iron; Iron chelators; Iron overload; Oxidative stress.

Figure 1

The Fenton reaction. The fenton reaction involves iron II (Fe ²⁺) reacting with hydrogen peroxide (H₂O₂) to yield iron II (Fe ³⁺) a hydroxyl radical (•OH) and a hydroxide ion (OH^-). The hydroxyl radical can induce lipid peroxidation; more reactive oxygen species (ROS) and oxidative stress; damage to DNA and other biomolecules; and if overexposed, carcinogenesis.

Figure 2

Iron regulation in normal and cancer cells. The iron regulatory proteins or involved in cellular metabolism include: Tf = transferrin; TfR1 = transferrin receptor; Fe^III-Tf = iron III bound to transferrin; FPN = ferroportin; LIP = labile iron pool; TAM = tumor associated macrophages; and HAMP = hepcidin. For a cancer cell compared to a normal cell: iron influx is higher, iron efflux is lower, LIP is higher, oxidative stress is higher, HAMP is higher, FPN is lower, and there are more TfR1 and extracellular sources of iron, including ferritin from tumor associated macrophages (TAM).

Figure 3

Potential therapeutic strategies for cancer prevention and cancer progression. Iron overload increases oxidative stress by the Fenton reaction. Cancer may be prevented in patients with iron overload by reducing iron (1) or reducing iron and oxidative stress (2). On the other hand, high oxidative stress and high iron represents the cancer cell phenotype. Cancer patients might benefit from iron depletion (3), an increase in ROS (4), or both (5). These effects can selectively induce apoptosis in tumor cells, which is especially vulnerable to iron depletion and increased oxidative stress.