1.
Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.
Calabrese, C, Panuzzo, C, Stanga, S, Andreani, G, Ravera, S, Maglione, A, Pironi, L, Petiti, J, Shahzad Ali, MS, Scaravaglio, P, et al
International journal of molecular sciences. 2020;(20)
Abstract
Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
2.
Chromium Supplementation and the Effects on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Jamilian, M, Asemi, Z
Annals of nutrition & metabolism. 2015;(1):42-8
Abstract
BACKGROUND The aim of the present study was to evaluate the beneficial effects of chromium intake on markers of insulin metabolism and lipid profiles in women with polycystic ovary syndrome (PCOS). METHODS In a prospective, randomized, double-blind, placebo-controlled trial, 64 women with PCOS were randomized to receive 200 µg chromium picolinate supplements (n = 32) or placebo (n = 32) for 8 weeks. Fasting blood samples were obtained at baseline and 8 weeks after the intervention to quantify markers of insulin metabolism and lipid concentrations. RESULTS Chromium supplementation in women with PCOS resulted in significant decreases in serum insulin levels (-3.6 ± 7.4 vs. +3.6 ± 6.2 µIU/ml, p < 0.001), homeostasis model of assessment-insulin resistance (HOMA-IR; -0.8 ± 1.6 vs. +0.9 ± 1.5, p < 0.001), homeostatic model assessment-beta cell function (HOMA-B; -15.5 ± 32.3 vs. +13.6 ± 23.1, p < 0.001), and a significant increase in quantitative insulin sensitivity check index (QUICKI) score (+0.02 ± 0.03 vs. -0.008 ± 0.02, p = 0.001) compared with the placebo. In addition, a trend toward a significant effect of chromium supplementation on decreasing serum triglycerides (-12.4 ± 74.4 vs. +15.2 ± 32.4 mg/dl, p = 0.05), very low-density lipoprotein-cholesterol (-2.5 ± 14.9 vs. +3.0 ± 6.5 mg/dl, p = 0.05), and cholesterol concentrations (-8.6 ± 21.9 vs. +0.7 ± 22.4 mg/dl, p = 0.09) was seen. CONCLUSIONS Eight weeks of chromium supplementation among PCOS women had favorable effects on markers of insulin metabolism.
3.
Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome.
Shenoy, N, Vallumsetla, N, Rachmilewitz, E, Verma, A, Ginzburg, Y
Blood. 2014;(6):873-81
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Abstract
Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.
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A case report of deferasirox-induced kidney injury and Fanconi syndrome.
Murphy, N, Elramah, M, Vats, H, Zhong, W, Chan, MR
WMJ : official publication of the State Medical Society of Wisconsin. 2013;(4):177-80
Abstract
Cases of kidney injury associated with the use of deferasirox chelation therapy during the course of treatment for iron overload have been reported infrequently. We present the case of a patient treated with deferasirox who had biopsy-proven tubular injury in the setting of clinical Fanconi syndrome. The patient required hospitalization for metabolic acidosis, electrolyte abnormalities, and associated symptoms. With supportive care and cessation of chelation therapy he improved, but has yet to fully recover. This is the first known case reporting biopsy-proven tubular damage in the setting of deferasirox use.