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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.
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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.
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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.
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The role of iron in patients after bone marrow transplantation.
de Witte, T
Blood reviews. 2008;:S22-8
Abstract
Haemopoietic stem cell transplantation (HSCT) is an important intervention for malignant and non-malignant blood diseases. However, HSCT is also associated with considerable morbidity and mortality, some of which may be related to iron overload. Levels of serum iron are elevated in patients undergoing HSCT as a result of disturbed iron metabolism, pre-transplantation blood transfusions, or cytotoxic therapy for conditioning before HSCT. The complications of iron overload in HSCT patients include infections, mucositis, chronic liver disease (fibrosis progression), sinusoidal obstruction syndrome, and idiopathic pneumonia syndrome. Iron overload has an adverse impact on survival in patients undergoing HSCT for beta-thalassaemia major or haematological malignancies including myelodysplastic syndromes. It has been suggested that all candidates for and all survivors of HSCT should be screened for iron overload at various time points before and after transplantation. Few studies of iron chelation therapy after HSCT have been reported, but one small study has indicated that deferoxamine is at least as effective as phlebotomy in reducing post-transplantation iron overload in patients with beta-thalassaemia major. The new oral chelator deferasirox may be better tolerated than phlebotomy or deferoxamine infusion, and two prospective phase II studies in patients with iron overload after HSCT are now recruiting candidates.
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Chromium picolinate for insulin resistance in subjects with HIV disease: a pilot study.
Feiner, JJ, McNurlan, MA, Ferris, RE, Mynarcik, DC, Gelato, MC
Diabetes, obesity & metabolism. 2008;(2):151-8
Abstract
AIM: Multidrug regimens in HIV disease are associated with an increased incidence of insulin resistance, by as much as 50%. Not only does insulin resistance predisposes subjects to diabetes but also it is associated with the metabolic syndrome and increased risk of cardiovascular disease. Previous studies suggest that chromium picolinate can improve insulin resistance in patients with type 2 diabetes. The objective was to study the efficacy and safety of chromium picolinate as a treatment of insulin resistance in subjects infected with HIV. METHODS The ability of chromium picolinate (1000 mug/day) to improve insulin sensitivity, determined with a hyperinsulinaemic-euglycaemic insulin clamp, was determined in eight HIV-positive subjects on highly active antiretroviral therapy. RESULTS The mean rate of glucose disposal during the clamp was 4.41 mg glucose/kg lean body mass (LBM)/min (range 2.67-5.50), which increased to 6.51 mg/kg LBM/min (range 3.19-12.78, p = .03), an increase of 25% after 8 weeks of treatment with chromium picolinate. There were no significant changes in blood parameters, HIV viral burden or CD4+ lymphocytes with chromium picolinate treatment. Two subjects experienced abnormalities of liver function during the study. Another subject experienced an elevation in blood urea nitrogen. CONCLUSIONS The study shows that chromium picolinate therapy improves insulin resistance in some HIV-positive subjects, but with some concerns about safety in this population.