Deferasirox

Cellular iron plays a crucial role in many crucial physiological processes. Excessive iron retention due to iron influx and efflux imbalance contributes to cancer development and proliferation, as well as malignant conversion. Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a crucial role in tumor invasion and metastasis, because this enzyme can degrade various extracellular matrix components and cleave membrane tethered proteins on the cell surface. Herein, we demonstrate that cellular iron regulates MT1-MMP-mediated proMMP-2 activation and thereby cancer cell invasion. Iron depletion downregulated MT1-MMP expression in cancer cells, accompanied by inhibition of proMMP-2 activation. Conversely, iron loading stimulated MT1-MMP expression and MT1-MMP-containing extracellular vesicle secretion, thereby promoting proMMP-2 activation, which was inhibited through antioxidant treatment. Iron chelator deferasirox suppressed cancer cell invasion but not fibroblasts. Thus, this study indicated that iron accumulation in cancer may contribute to not only cell proliferation but also invasion by activating the MT1-MMP-MMP-2 axis.

Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload.