Drug Discovery Opinion

The energy demands of rapidly proliferating cancer cells require high levels of nutrients, including iron. Since cells are sensitive to free iron, they utilise iron storage proteins to protect themselves. Scientists at the German Cancer Research Center (DFKZ) and University Medical Center Mannheim, studying Sézary’s disease, have now shown that manipulation of free intracellular iron can induce apoptosis in T-cell lymphomas.

Sézary’s disease is an aggressive and ultimately fatal type of cutaneous T-cell lymphoma that is resistant to currently available treatments. Apoptosis resistance in leukemias and lymphomas is mediated by aberrant signalling of the NF-_κB pathway. The researchers have demonstrated that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-_κB pathway is a result of increased free intracellular iron and reactive oxygen species (ROS). Using T-cells from Sézary patients they show that inhibition of constitutively active NF-_κB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. The involvement of FHC was confirmed by direct down-regulation using siRNA.

Importantly, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-_κB inhibition.

The work, published in the journal Cancer Research, suggests FHC as a novel target for therapeutic intervention in lymphoma.

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