This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

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OBJECTIVE -The aim of this study was to determine the distribution of serum extracellular superoxide dismutase (EC-SOD) concentrations in patients with type 2 diabetes and to assess whether increased EC-SOD concentration is associated with the development of diabetic vascular complications.RESEARCH DESIGN AND METHODS -Serum EC-SOD concentrations were determined in 222 patients with type 2 diabetes and 75 healthy control subjects by an enzyme-linked immunosorbent assay. All subjects had the EC-SOD domain genotyped.RESULTS -The serum EC-SOD concentrations showed a distinct bimodal distribution in both patients with diabetes and control subjects. All subjects with the high-level phenotype carried the Arg213Gly mutation. The frequency of this variant was similar in the diabetes and control groups. Within the group of subjects with the common EC-SOD phenotype, the serum EC-SOD concentration (mean Ϯ SE) was significantly higher in patients with type 2 diabetes (99.3 Ϯ 1.3 ng/ml) compared with the control subjects (68.4 Ϯ 2.3 ng/ml, P Ͻ 0.01). Stepwise multiple regression analysis of the data from the diabetic common phenotype group showed a significant relationship between serum EC-SOD concentration and duration of diabetes (F ϭ 5.31), carotid artery intimal-media thickness (F ϭ 8.24), and severity of nephropathy (F ϭ 16.05) and retinopathy (F ϭ 4.43).CONCLUSIONS -We observed a strong relationship between the serum concentration of EC-SOD and the severity of both micro-and macrovascular diabetic complications. These findings suggest that serum EC-SOD concentration levels may be a marker of vascular injury, possibly reflecting hyperglycemia-induced oxidative injury to the vascular endothelium and decreased binding of EC-SOD to the vascular wall. Diabetes Care 26:1246 -1250, 2003H yperglycemia is a major factor in the development of diabetic complications, although the mechanisms of how increased glucose levels contribute to these changes have not been fully elucidated. Adverse biochemical changes associated with hyperglycemia include increased flux of glucose through the polyol pathway, enhanced nonenzymatic glycation, and activation of the diacylglycerol-protein kinase C pathway. Hyperglycemia may also result in increased production of the reactive oxygen species within numerous biochemical pathways that have the potential to initiate adverse changes in endothelial function (1).Extracellular superoxide dismutase (EC-SOD) is a secretory glycoprotein with an affinity for heparan-like substances (2-4), and it is the principal enzymatic scavenger of superoxide in the extracellular space (5). It has been shown that Ͼ99% of the enzyme is bound to heparan sulfate proteoglycans in vascular walls and to a lesser extent within the interstitium, and Ͻ1% is contained within the circulation in equilibrium between the plasma phase and the glycocalyx of the endothelium (6 -8). Molecular genetic studies have shown that a single-base substitution causing exchange of glycine for arginine-213 (Arg213Gly) in the heparin binding domain of...

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.