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1.
Dysregulation of iron metabolism in cancer stem cells.
Recalcati, S, Gammella, E, Cairo, G
Free radical biology & medicine. 2019;:216-220
Abstract
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells endowed with stem-like properties. Importantly, CSCs can survive current standard therapies, resulting in metastatic disease and tumor recurrence. Here we describe the alterations of iron homeostasis occurring in CSCs, which in general are characterized by high intracellular iron content. Importantly, abnormalities of iron metabolism correlate with faster tumor growth and adverse prognosis in cancer patients. In line with the dependence of cancer on iron, we also discuss iron-dependent mechanisms as druggable pathways, as iron chelators have been considered for tumor therapy and new molecules currently proposed and studied as antineoplastic drugs may impinge on iron and its capacity to promote oxidative stress to have therapeutic value in cancer.
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2.
Strategies for managing transfusional iron overload: conventional treatments and novel strategies.
Sheth, S
Current opinion in hematology. 2019;(3):139-144
Abstract
PURPOSE OF REVIEW For individuals who have transfusion-dependent anemia, iron overload is the long-term complication, which results in significant morbidity. Ameliorating this is now the biggest unmet need. This review specifically addresses this issue. RECENT FINDINGS Over the last decade or so, major advances in the treatment of these individuals, has resulted from novel strategies aimed at reducing transfusion requirement as well as optimizing chelation therapy. This review will summarize these advances and provide insights into some of the therapies in the pipeline. Strategies aimed at reducing transfusion requirement include modulation of erythropoietic regulation by reducing ineffective red cell production through activin trapping, as well as stem cell gene modification approaches, which aim for a cure, and transfusion independence. Refined means of assessing tissue iron and the introduction of oral chelators have facilitated tailoring chelation regimens with closer monitoring and improved compliance. Newer approaches to ameliorate iron toxicity have focused on the hepcidin pathway, all of which would result in increased hepcidin levels and reduction of iron absorption from the intestine, sequestration of iron in normal storage sites and reduced exposure of more susceptible organs, such as the heart and endocrine organs, to the toxic effects of increased iron. SUMMARY These advances offer the promise of improved management of transfusion-dependent individuals.
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3.
Management of the aging beta-thalassemia transfusion-dependent population - The Italian experience.
Pinto, VM, Poggi, M, Russo, R, Giusti, A, Forni, GL
Blood reviews. 2019;:100594
Abstract
Thalassemia is among the most common monogenic diseases worldwide. Stem cell transplantation can be curative but is reserved for young patients, as probably gene therapy will be in the future. Adult thalassemia patients are treated with transfusion therapy and iron chelation, and improvements in the safety of transfusion protocols, use of iron chelation, monitoring of iron overload, and management of comorbidities have substantially prolonged survival, increasing the proportion of adult patients in the thalassemic population. However, older patients are more likely to develop multiple disease-related morbidities, including osteoporosis, endocrine disorders, liver disease, renal dysfunction, and cancer. Thus, the main objective of this article is to describe new challenges posed by the increasing life expectancy of patients with thalassemia, focusing on data from Italy where there is a well-documented history of thalassemia management. It is hoped that the mortality and morbidity benefits already seen in patients with thalassemia will continue to improve with ongoing advances in the quality of treatment.
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4.
Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: Clinical data, potential mechanisms, and outstanding questions.
Leitch, HA, Gattermann, N
Critical reviews in oncology/hematology. 2019;:54-72
Abstract
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.
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5.
Iron and liver fibrosis: Mechanistic and clinical aspects.
Mehta, KJ, Farnaud, SJ, Sharp, PA
World journal of gastroenterology. 2019;(5):521-538
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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6.
New Insights into Oxidative Damage and Iron Associated Impairment in Traumatic Brain Injury.
Toro-Urrego, N, Turner, LF, Avila-Rodriguez, MF
Current pharmaceutical design. 2019;(45):4737-4746
Abstract
Traumatic Brain Injury is considered one of the most prevalent causes of death around the world; more than seventy millions of individuals sustain the condition per year. The consequences of traumatic brain injury on brain tissue are complex and multifactorial, hence, the current palliative treatments are limited to improve patients' quality of life. The subsequent hemorrhage caused by trauma and the ongoing oxidative process generated by biochemical disturbances in the in the brain tissue may increase iron levels and reactive oxygen species. The relationship between oxidative damage and the traumatic brain injury is well known, for that reason, diminishing factors that potentiate the production of reactive oxygen species have a promissory therapeutic use. Iron chelators are molecules capable of scavenging the oxidative damage from the brain tissue and are currently in use for ironoverload- derived diseases. Here, we show an updated overview of the underlying mechanisms of the oxidative damage after traumatic brain injury. Later, we introduced the potential use of iron chelators as neuroprotective compounds for traumatic brain injury, highlighting the action mechanisms of iron chelators and their current clinical applications.
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7.
Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity.
Moussa, RS, Park, KC, Kovacevic, Z, Richardson, DR
Free radical biology & medicine. 2019;:276-294
Abstract
Iron (Fe) has become an important target for the development of anti-cancer therapeutics with a number of Fe chelators entering human clinical trials for advanced and resistant cancer. An important aspect of the activity of these compounds is their multiple molecular targets, including those that play roles in arresting the cell cycle, such as the cyclin-dependent kinase inhibitor, p21. At present, the exact mechanism by which Fe chelators regulate p21 expression remains unclear. However, recent studies indicate the ability of chelators to up-regulate p21 at the mRNA level was dependent on the chelator and cell-type investigated. Analysis of the p21 promoter identified that the Sp1-3-binding site played a significant role in the activation of p21 transcription by Fe chelators. Furthermore, there was increased Sp1/ER-α and Sp1/c-Jun complex formation in melanoma cells, suggesting these complexes were involved in p21 promoter activation. Elucidating the mechanisms involved in the regulation of p21 expression in response to Fe chelator treatment in neoplastic cells will further clarify how these agents achieve their anti-tumor activity. It will also enhance our understanding of the complex roles p21 may play in neoplastic cells and lead to the development of more effective and specific anti-cancer therapies.
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8.
New targeted therapies and diagnostic methods for iron overload diseases.
Kolnagou, A, Kontoghiorghe, CN, Kontoghiorghes, GJ
Frontiers in bioscience (Scholar edition). 2018;(1):1-20
Abstract
Millions of people worldwide suffer from iron overload toxicity diseases such as transfusional iron overload in thalassaemia and hereditary haemochromatosis. The accumulation and presence of toxic focal iron deposits causing tissue damage can also be identified in Friedreich's ataxia, Alzheimer's, Parkinson's, renal and other diseases. Different diagnostic criteria of toxicity and therapeutic interventions apply to each disease of excess or misplaced iron. Magnetic resonance imaging relaxation times T2 and T2* for monitoring iron deposits in organs and iron biomarkers such as serum ferritin and transferrin iron saturation have contributed in the elucidation of iron toxicity mechanisms and pathways, and also the evaluation of the efficacy and mode of action of chelating drugs in the treatment of diseases related to iron overload, toxicity and metabolism. Similarly, histopathological and electron microscopy diagnostic methods have revealed mechanisms of iron overload toxicity at cellular and sub-cellular levels. These new diagnostic criteria and chelator dose adjustments could apply in different or special patient categories e.g. thalassaemia patients with normal iron stores, where iron deficiency and over-chelation toxicity should be avoided.
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9.
Interaction of Transfusion and Iron Chelation in Thalassemias.
Porter, JB, Garbowski, MW
Hematology/oncology clinics of North America. 2018;(2):247-259
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Abstract
The relationship between blood transfusion intensity, chelatable iron pools, and extrahepatic iron distribution is described in thalassemia. Risk factors for cardiosiderosis are discussed with particular reference to the balance of transfusional iron loading rate and transferrin-iron utilization rate as marked by plasma levels of soluble transferrin receptors. Low transfusion regimens increase residual erythropoiesis allowing for apotransferrin-dependent clearance of non-transferrin-bound iron species otherwise destined for myocardium. The impact of transfusion rates on chelation dosing required for iron balance is also shown.
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10.
Iron overload cardiomyopathy: from diagnosis to management.
Díez-López, C, Comín-Colet, J, González-Costello, J
Current opinion in cardiology. 2018;(3):334-340
Abstract
PURPOSE OF REVIEW Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. RECENT FINDINGS The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. SUMMARY IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.