Drug Developers Eye Cancer Iron Storage Proteins

The necessity for rapidly growing cancer cells to sequester high levels of iron presents drug developers with the opportunity of targeting the iron storage proteins that protect the cells from reactive oxygen species (ROS) that can trigger cell death (apoptosis).

Cancer cells that carry a mutated form of the nuclear factor kappa-B (NF-kappa-B) signaling pathway are able to control levels of intracellular iron by increasing the amount of ferritin heavy chains (FHCs), proteins that store the iron and prevent the formation of ROS.

Investigators from the German Cancer Research Center (DFKZ; Heidelberg, Germany) reported in the March 15, 2009, edition of the journal Cancer Research that inhibition of active NF-kappa-B triggered down-regulation of FHCs, which caused an increase of free intracellular iron. This increase induced massive generation of ROS. Direct downregulation of FHCs by siRNA caused ROS-dependent cell death, while in a different model system high concentrations of ROS induced cell death of malignant T cells.

T cells isolated from healthy donors did not display downregulation of FHCs, and therefore, did not show an increase in iron and cell death upon NF-kappa-B inhibition. In addition, in a mouse T cell lymphoma model, the inhibition of NF-kappa-B and subsequent down-regulation of FHCs significantly delayed tumor growth.

Based on these findings, the investigators concluded that, "Our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-kappa-B signaling.”

Related Links:
German Cancer Research Center