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Rhabdomyosarcoma (RMS) is an aggressive rare neoplasm that derives from mesenchymal cells, which frequently develops resistance to the current therapies and the formation of metastases. Thus, new therapies are needed. The alteration of iron metabolism in cancer cells was effective in reducing the progression of many tumors but not yet investigated in RMS. Here we investigated the effect of iron modulation in RMS both in vitro and in vivo. We first characterized the most used RMS cell lines representing the most common subtypes, embryonal (ERMS, RD cells) and alveolar (ARMS, RH30 cells), for their iron metabolism, in basal condition and in response to its modulation. Then we investigated the effects of both iron overload and chelation strategies in vitro and in vivo. RMS cell lines expressed iron-related proteins, even if at lower levels compared to hepatic cell lines and they are correctly modulated in response to iron increase and deprivation. Interestingly, the treatment with different doses of ferric ammonium citrate (FAC, as iron source) and with deferiprone (DFP, as iron chelator), significantly affected the cell viability of RD and RH30. Moreover, iron supplementation (in the form of iron dextran) or iron chelation (in the form of DFP) were also effective in vivo in inhibiting the tumor mass growth both derived from RD and RH30 with iron chelation treatment the most effective one. All the data suggest that the iron modulation could be a promising approach to overcome the RMS tumor growth. The mechanism of action seems to involve the apoptotic cell death for both iron supplementation and chelation with the concomitant induction of ferroptosis in the case of iron supplementation. [ABSTRACT FROM AUTHOR]

β-thalassemia, a congenital genetic hematological disorder characterized by the decrease or absence of β-globin chains, leads to a decrease in levels of Hemoglobin A. The affected individuals can be categorized into two cohorts based on transfusion dependency: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). Remarkably, despite the primary pathology lying in β-globin chain depletion, β-thalassemia also exhibits an intriguing association with iron overload. Iron metabolism, a tightly regulated physiological process, reveals a complex interplay in these patients. Over time, both cohorts of β-thalassemic individuals develop iron overload, albeit through distinct mechanisms. Addressing the diverse complications that arise due to iron overload in β-thalassemic patients, the utilization of iron chelators has gained a lot of significance. With varying efficacies, routes of administration, and modes of action, different iron chelators offer unique benefits to patients. In the Indian context, three commercialized iron chelators have emerged, showcasing a high adherence rate to iron chelator-based treatment regimens among β-thalassemic individuals. In this review, we explore the intriguing connection between β-thalassemia and iron overload, shedding light on the intricate mechanisms at play. We delve into the intricacies of iron metabolism, unveiling the distinct pathways leading to iron accumulation in these patients. Additionally, the therapeutic efficacy of different iron chelators in managing iron overload complications is mentioned briefly, along with the guidelines for their usage in India. Through this comprehensive analysis, we aim to deepen our understanding of β-thalassemia and iron overload, paving the way for optimized treatment strategies. Ultimately, our findings provide valuable insights into improving the care and outcomes of individuals affected by β-thalassemia. [ABSTRACT FROM AUTHOR]

Introduction and aim. The novel advancements of upcoming iron regulators used to treat diabetic nephropathy have implicated a common manifestation of combination chelation therapy used to eliminate end-stage renal disease associated with inflammation and iron imbalance that is altered by renal iron absorption. However, iron accumulation in the clustered kidneys that filter blood may cause problems that affect diabetic blood sugar regulation. Material and methods. A well-designed method was employed to discover relevant research publications on iron chelators and their potential to treat diabetic nephropathy. "Iron chelators", "diabetic nephropathy", "end-stage renal disease", and "chelation therapy" were searched in Google Scholar, Web of Science, PubMed, and EMBASE. Analysis of literature. Although the specific etiology and development have not been fully explored, emerging evidence on iron pathophysiology helps comprehend the pathogenesis of acute kidney damage and chronic kidney disease, which crucially provides novel iron chelation therapy techniques. Ferroptosis and hepcidin marker proteins increase oxidative/nitrifying stress and kidney injury. Iron chelator medicines including deferoxamine, deferasirox, and deferiprone were tested as prophylactic strategies. Conclusion. This article covers both preclinical and clinical aspects of iron chelators to avoid diabetic nephropathy, including novel iron therapies that must be reviewed when selecting dosing regimens. [ABSTRACT FROM AUTHOR]

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, which inhibit the final step of heme biosynthesis, thereby increasing the protoporphyrin IX concentration. In the presented work, we studied thiosemicarbazone derivative, which is a universal enhancer of the phototoxic effect. We examined several genes that are involved in the transport of the heme substrates and heme itself. The results indicate that despite an elevated level of ABCG2, which is responsible for the PpIX efflux, its concentration in a cell is sufficient to trigger a photodynamic reaction. This effect was not observed for 5-ALA alone. The analyzed cell lines differed in the scale of the effect and a correlation with the PpIX accumulation was observed. Additionally, an increased activation of the iron transporter MFNR1 was also detected, which indicated that the regulation of iron transport is essential in PDT. [ABSTRACT FROM AUTHOR]

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated. [Display omitted] • Mitophagy participate in maintaining mitochondrial and cellular functionality. • Mitophagy dysregulation is deeply associated with serious pathogenesis. • Iron homeostasis and mitophagy regulation are deeply interconnected. • Decrease in free cellular/mitochondrial iron level can induce mitophagy. • Mitophagy normalization is one of the therapeutic effects of iron chelators. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common type of cancer in the world. It is characterized by complex crosstalk between various signaling pathways, as a result of which it is highly challenging to identify optimal therapeutic targets and design treatment strategies. In this study, we tested the effect of 700 compounds on the CRC cell line HT-29 by using the sulforhodamine B assay and screened out 17 compounds that exhibited high toxicity (indicated by an inhibition rate of ≥75 % when applied at a concentration of 10 µM) against the HT-29 cell line. Next, we investigated the mechanisms underlying the effects of these 17 highly toxic compounds. The results of ferroptosis analysis and electron microscopy showed that compounds 575 and 578 were able to significantly reverse RSL3-induced increase in ferroptosis, while compound 580 had a less pronounced ferroptosis-regulating effect. In subsequent experiments, western blotting showed that compounds 575, 578, and 580, which belong to a class of meroterpene-like compounds that affect ferroptosis, do not induce autophagy or apoptosis in the CRC cell line. Instead, Fe2+ chelation experiments showed that these three compounds can serve as iron chelators by chelating Fe2+ at a 1:1 (chelator: Fe2+) ratio. Specifically, the aldehyde and hydroxyl groups of the benzene ring in these compounds may chelate Fe2+, thus reducing Fe2+ levels in cells and inhibiting ferroptosis. These results indicate that these novel meroterpene-like compounds are potential therapeutic small-molecule candidates for targeting ferroptosis in tumors. [Display omitted] • Novel meroterpene-like compounds had no effect on apoptosis autophagy. • Novel meroterpene-like compounds rescue ferroptosis via Fe2+ chelation. • Novel meroterpene-like compounds be a valuable candidate for the anti-cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa. [ABSTRACT FROM AUTHOR]

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment. [ABSTRACT FROM AUTHOR]

Ferroptosis is a newly discovered cell death form originates from iron-dependent lipid peroxide accumulation, which differs from traditional apoptosis and necrosis. This is characterized by cytological changes including cell death, shrinkage of cell volume and increased mitochondrial membrane density. Morphologically, mitochondrial membrane condensation, impairment or destruction of the mitochondria crista, and mitochondrial membrane rupture, and smaller mitochondria than normal mitochondria can be seen. Ferroptosis can be induced by class of two small molecule substances known as class 1 and class 2 ferroptosis inducers. In addition to these substances, it can also be induced by drugs such as Sorafenib and artemisine derivative. In cancer cells and some normal cells, such as renal tubule cells, it can be triggered by these drugs and class 1 and 2 ferroptosis inducers. Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, increased endoplasmic reticulum stress, and inhibition of the cystine-glutamate delivery system have been implicated in the induction of ferroptosis. This process is caused by the accumulation of lipid peroxidation products and reactive oxygen species (ROS) derived from iron metabolism. Ferroptosis may be inhibited by iron chelators (eg, Deferoxamine) and lipid peroxidation inhibitors (eg, Ferrostatin). Ferroptosis plays an undeniable role in the proliferation of some tumor cells such as lymphocytoma, pancreatic ductal cell cancer, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Ferroptosis was first described in 2012 as an iron- and lipid peroxidation-dependent form of regulated cell death. Since its initial description, these two characteristics have informed numerous cell culture studies where inhibitors of lipid peroxidation and/or iron chelators have been shown to prevent cell death induced by a wide range of insults. However, it is not clear whether these two characteristics are sufficient to distinguish ferroptosis from other forms of regulated cell death. Thus, the primary goal of this study was to determine whether a unique combination of features could be identified that would provide an approach to more clearly separate ferroptosis from other forms of regulated cell death. To this end, multiple pharmacological inhibitors based on a variety of studies were tested. Many of these inhibitors were previously shown to protect cells from oxytosis, a regulated cell death pathway that mechanistically overlaps with ferroptosis and is induced by some of the same chemicals as ferroptosis. These inhibitors were not only tested against both known ferroptosis and oxytosis inducers but also a number of other insults that have been suggested to induce ferroptosis. The results show that a pharmacological fingerprint for ferroptosis can be established and used to categorize toxic insults into those that overlap with oxytosis/ferroptosis and those that do not. [Display omitted] • Identification of a set of inhibitors that protect from multiple, well characterized inducers of oxytosis/ferroptosis. • Demonstration that most of these inhibitors do not protect from other inducers of oxidative stress-mediated cell death. • Protection from cell death by iron chelators and radical trapping antioxidants is not specific to oxytosis/ferroptosis. • Inhibitor fingerprint is applicable to several distinct cell types and a non-canonical inducer of oxytosis/ferroptosis. [ABSTRACT FROM AUTHOR]

Objectives: The present study was aimed to compare the adherence and satisfaction with deferoxamine (Desferal®) versus deferasirox (Exjade®), a novel oral iron chelator, in patients with transfusion-dependent beta-thalassemia. Patients and Methods: In this cross-sectional, single-center study, 108 homozygous βthalassemia major patients aged between 3-21 years old were enrolled. They were on regular blood transfusions and iron chelators (either deferoxamine or deferasirox) for about three months. Another fifty-six apparently healthy non-thalassemic subjects were enrolled as a control group. Results: Adherence and satisfaction wereassessed byusing a simplequestionnaire establishedduring an interviewwithpatientsortheirparents.The serumferritin level was measuredbythe ELISAmethod. Our findings showed that adherence and satisfaction in the deferasirox group were more than that with deferoxamine group patients. Serum ferritin level in the deferasirox group was significantly lower than in the deferoxamine group at (p<0.001). while the control group was significantly lower than both patients groups at (p<0.001). Patients on deferasirox had lower adverse effects than the deferoxamine group since deferoxamine produce irritation and pain at the injection site for the patients. Conclusion: Our findings concluded that deferasirox is an effective iron chelator as deferoxamine but with better adherence and satisfaction than deferoxamine. Deferasirox can be used as a preferred iron chelator therapy in iron-overload patients with beta-thalassemia. [ABSTRACT FROM AUTHOR]

While the etiology of non-familial Parkinson's disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10–20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation. [ABSTRACT FROM AUTHOR]

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress, and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal degeneration in Parkinson's disease (PD); however, a link between these features remains unconfirmed. Using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxidative stress and promoting protein aggregation. We demonstrate the neuroprotective potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds' iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also demonstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropathological hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity. [ABSTRACT FROM AUTHOR]

Iron is an indispensable element for the development of almost all living things, and its acquisition is a key process for organisms. However, the low solubility of Fe3+ in aqueous systems causes its reduced bioavailability. Thus, organisms confronted with low iron availability have developed several iron scavenging strategies, and one of these ways is to use low molecular‐weight organic molecules, which are specific ferric ion chelators called siderophores. These compounds exhibit an extremely high affinity and specificity for Fe3+ and are produced and secreted by bacteria, fungi, and plants. Recently, siderophores have attracted much attention due to their applications in areas such as microbial ecology, specific crop production, detoxification of heavy metal‐contaminated samples, biodetection of metals, and the selective delivery of antibiotics to resistant bacterial strains. Nevertheless, the limited supply of these natural products has been an obstacle that needs to be overcome. This review provides an overview of the contemporary developments in the total synthesis of naturally occurring siderophores during the last two decades. [ABSTRACT FROM AUTHOR]

Objectives: Beta-thalassemias are a group of recessively autosomal inherited disorders of hemoglobin synthesis, which, due to mutations of the beta-globin gene, lead to various degrees of defective beta-chain production, an imbalance in alpha/beta-globin chain synthesis, ineffective erythropoiesis, and anemia. Improved survival in thalassemic patients has led to the emergence of previously unrecognized complications, such as renal disease. Methods: A comprehensive literature review through PubMed was undertaken to summarize the published evidence on the epidemiology and pathophysiology of renal disease in thalassemia. Literature sources published in English since 1990 were searched, using the terms beta-thalassemia, renal disease. Results: Renal disease is considered to be the 4th cause of morbidity among patients with transfusion dependent thalassemia. Chronic anemia, hypoxia and iron overload are the main mechanisms implicated in development of renal injury, whereas several studies also suggested a contributive role of iron chelators. Discussion and Conclusion: Kidney disease may develop through progressive renal tubular and glomerular damage; thus, its early recognition is important in order to prevent and/or reverse deterioration. This review will provide an insight on the involved mechanisms implicated in kidney disease in thalassemic patients and will discuss the updates on diagnosis and prevention of renal complications in thalassemia. [ABSTRACT FROM AUTHOR]

Background and aims:Thalassemia patients are predisposed to septicemia due to iron overload. The iron chelators have a potential role in the treatment of septicemia. This study was conducted to investigate the in vitro effect of iron chelators, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFS) on the growth of effective bacteria (Staphylococcus aureus, Yersinia enterocolitica, and Pseudomonas aeruginosa) and their synergistic effect with each other and antibiotics. Materials and Methods: Five bacterial strains were incubated in the presence of seven chelators in Mueller Hinton agar and the number of colonies was recorded for each sample. Antibiotic discs were placed in the plates. Susceptibility to antibiotics was assessed by disc diffusion method (Kirby-Bauer test) and also the zone inhibition around the disc was measured in mm after incubating the relevant plate at 37°C for a day. Results: The growth of all the studied bacteria increased in the presence of iron and was inhibited in the presence of different chelators. Chelators and antibiotics had synergistic effects on growth inhibition of Escherichia coli, S. aureus, and P. aeruginosa in culture medium, while the growth inhibition of Y. enterocolitica was seen in the presence of deferiprone and deferasirox combination. Conclusion: Chelators in combination with antibiotics exert synergistic effects on growth inhibition of prevalent bacteria (except for Y. enterocolitica). [ABSTRACT FROM AUTHOR]

Cardiac complications including arrhythmia and especially atrial fibrillation (AF) are common causes of death in β‐thalassemia patients. The main factor in the etiopathogenesis of these complications is iron overload, which results in increased oxidative stress. Although there is a known association between cardiac complications and iron overload in β‐thalassemia patients, there is no comprehensive review on AF and excessive iron with a focus on oxidative stress in these patients. The aim of this article was to review the different aspects of AF in β‐thalassemia patients with a focus on the prevention and treatment of AF by using iron chelators and/or anti‐oxidants. AF in β‐thalassemia patients is more common than in the general population. One of the most important causes of AF is cardiac iron overload and the harmful effects of increased oxidative stress. Iron‐induced AF can be reversed by using an intensive iron chelation regimen. Based on a few experimental studies, the combination of iron chelators with some anti‐oxidants, including NAC, vitamin C, and acetaminophen, can lead to improved cardiac protection. However, the effect of such combinations on cardiac arrhythmias should be further evaluated with animal and human studies. [ABSTRACT FROM AUTHOR]

Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells. We will also focus on the potential mechanisms causing cellular dysfunction in Friedreich Ataxia and on the potential use of the iron chelator deferiprone as a therapeutic agent for this disease. [ABSTRACT FROM AUTHOR]

Abstract Background Iron overload is a major issue for transfusion-dependent patients. Repeated transfusions result in the loading of large amounts of haem-derived iron on macrophages, and the haemin in turn induces cell death and the generation of reactive oxygen species (ROS) in both murine macrophages and human monocytic THP-1 cells. This haemin-induced cell death process has been shown to be iron-dependent. Thus, we hypothesized that haemin-induced THP-1 cell death is a result of ferroptosis, an iron-dependent mechanism of cell death regulation. Material and methods Human monocytic THP-1 cells were treated with haemin, and haemin-induced cell death and ROS generation were assessed using flow cytometry. Results Haemin-induced THP-1 cell death showed a necrosis pattern, and treatment with iron chelators suppressed both haemin-induced cell death and ROS generation. Treatment with ferrostatin-1, a ferroptosis inhibitor, suppressed haemin-induced cell death without affecting ROS generation, whereas erastin, a ferroptosis inducer, enhanced both haemin-induced cell death and ROS generation. Discussion Our findings support haemin-induced cell death as an example of ferroptosis. Therefore, ferroptosis inhibitors may be useful for the treatment or prevention of transfusion iron overload. [ABSTRACT FROM AUTHOR]

Methyl substituted 3-hydroxypyridin-4(1 H)-ones have been synthesized. The p Ka values and Fe3+ affinity constants of these ligands were studied. The introduction of an electron-donating methyl group at a different position of pyridinone ring markedly influences the p Ka values of 3-hydroxy and 4-oxo groups. The pFe3+ values were also affected and are in the range of 17.6-20.7. The findings can be used to guide a design of 3-hydroxypyridin-4-ones with desirable p Ka and pFe3+ values. [ABSTRACT FROM AUTHOR]

The study showed that dinitrosyl iron complex (NO)Fe(RS) containing the thiolate ligands, which is the basic physiological donor of NO, can transfer NO to other molecule only at the moment of rearrangement. This rearrangement can occur during interaction of the complex with more effective iron chelators than the thiolate ligands. In the absence of NO trap, a new complex is formed with a new ligand. NO transfer to a trap can also occur under the action of the agents such as mercury salts or ROS, which interact with the thiolate ligands. Probably, the ligands in the dinitrosyl iron complexes are the structures responsible for interaction of these complexes with physiological targets and for specificity and effectiveness of this interaction. [ABSTRACT FROM AUTHOR]

Objective: To evaluate efficacy, safety and utilization pattern of deferasirox in paediatric patients of transfusion dependant β Thalassemia Major at a tertiary care teaching hospital in Gujarat. Materials and Methods: This observational, prospective-retrospective, single centre, continuous study was conducted in a tertiary care teaching hospital among paediatric patients of transfusion dependent β Thalassemia Major. Patients treated with deferasirox for not more than 12 weeks were enrolled. Details of blood transfusions, relevant investigations performed every 3 weeks and 3 months and drugs used were recorded in a pretested case record form. Parents were provided with a diary to record the details of ADRs. Data were analyzed for demographic characteristics, number and mean volume of blood transfusions, changes in serum ferritin and iron levels, number and types of ADRs and progression, causality, severity and preventability of ADRs. Results: Of the 60 patients enrolled, one patient was lost to follow up and four withdrew their consent. Of the remaining 55 patients, 36 were boys and 19 were girls (mean age: 6 ± 3.14 years), including patients of 1-3 years (11), 4-6 years (24), 7-10 years (12) and 11-12 years (8). Thirty six patients were born of consanguineous marriages. Adherence to blood transfusion guidelines and deferasirox prescribing and administration guidelines was observed. A serial and significant decrease in mean serum ferritin and serum iron at 3 weeks and 3 months with deferasirox treatment was observed in all age groups except that of 11-12 years. A total of 117 ADRs were observed in 52 patients from 19498 doses, most common being diarrhea (24), raised serum creatinine (15), raised hepatic enzymes (14), abdominal pain (14) and rashes (14). A reduction in dose was required in 32 cases, while a temporary stoppage was indicated in 41 cases. Deferasirox was the possible and probable cause of 65 and 51 ADRs respectively as assessed by WHO-UMC scale. Majority of ADRs were definitely preventable and mild in nature. Conclusion: β Thalassemia Major is more common in males. A rational prescribing of deferasirox was observed. Deferasirox effectively reduced serum ferritin and serum iron levels in these patients. [ABSTRACT FROM AUTHOR]

Background: Thalassemia is a chronic, inherited blood disorder, which in its most severe form, causes lifethreatening anemia. Thalassemia patients not only engage with difficulties of blood transfusion and iron chelating therapy but also have some social challenges and health threatening factors. There are some reports on quality of life in thalassemia patients around the world from southeast of Asia to Italy in Europe and United States. In this study, we tried to evaluate and compare Health Related Quality of life (HRQoL) and the health utility in beta thalassemia major patients receiving different types of iron chelators and living in different socio-economical situations. Subjects and Methods: EQ-5D-3L accompanied by a Visual Analogue Scale (VAS) questionnaire was used. The respondents were patients with beta thalassemia major that were at least 12 years old selected from 3 provinces of Sistan-Blouchestan, Fars and Mazandaran. Comorbidities including heart complication, Diabetes Mellitus and Hepatitis and also types of iron chelators (oral, injection, combination of both) were also asked. Cross tab and ANOVA analysis conducted to evaluate each dimension score and health utility differences between provinces, iron chelation methods, comorbidities, age group and gender. Results: 528 patients answered the questionnaires. The health utility of patients that received oral iron chelator were 0.87 ± .01 for oral iron chelators versus 0.81 ± .01 for injection dosage form (p<0.05). Increase in age was accompanied by decrease in health utility. Females faced more usual activity problems, anxiety and depression. Heart problems were more prevalent in males. Conclusion: This study suggests that the quality of life of beta thalassemia major patients is dependent on type of iron chelation treatment which they received, the gender they have, the comorbidities they suffer and socio-economical situations they live in. [ABSTRACT FROM AUTHOR]

Background Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). Aim To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload. Methods This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups ( n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not ( n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Results Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. Conclusions Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events. [ABSTRACT FROM AUTHOR]

This work reports a facile sonochemical route in the synthesis of nano particle of deferasirox for the first time. One application of nanotechnology is in improvement of available treatments for various diseases. Deferasirox (ICL670 or Exjade) is a tridentate chelating agent for removing transfusion overload iron in thalassemia patients. In the present work, deferasirox was prepared in nano size by using of ultrasound waves. The effects of amount and reaction time on the size of deferasirox were investigated. These parameters were optimized at various amounts and different reaction times. Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) studies show that the deferasirox in nature structure does not change during the reaction. The results show that the finest particle is related to the following conditions: 45min, time reaction and 0.1g, amount of deferasirox. Therefore, the ultrasonic bath method has a fundamental role in the preparation of deferasirox in nano scale. This method is simple, relatively fast and low cost. [ABSTRACT FROM AUTHOR]

Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme required for hydroxylation of the aminobutyl side chain of deoxyhypusine in eukaryotic translation initiation factor 5A (eIF-5A), the second step in hypusine biosynthesis. DOHH has been recently identified in P. falciparum and P. vivax. Both enzymes have very peculiar features including E-Z type HEAT-like repeats and a diiron centre in their active site. Both proteins share only 26 % amino acid identity to the human paralogue. Hitherto, no X-ray structure exists from either enzyme. However, structural predictions based on the amino acid sequence of the active site in comparison to the human enzyme show that four conserved histidine and glutamate residues provide the coordination sites for chelating the ferrous iron ions. Recently, we showed that P. vivax DOHH is inhibited by zileuton ( N-[1-(1-benzothien-2-yl)ethyl]- N-hydroxyurea), a drug that is known for inhibiting human 5-lipoygenase (5-LOX) by the complexation of ferrous iron. A novel discovery program was launched to identify inhibitors of the P. falciparum DOHH from the Malaria Box, consisting of 400 chemical compounds, which are highly active in the erythrocytic stages of Malaria infections. In a first visual selection for potential ligands of ferrous iron, three compounds from different scaffold classes namely the diazonapthyl benzimidazole MMV666023 (Malaria Box plate A, position A03), the bis-benzimidazole MMV007384 (plate A, position B08), and a 1,2,5,-oxadiazole MMV665805 (plate A, position C03) were selected and subsequently evaluated in silico for their potential to complex iron ions. As a proof of principle, a bioanalytical assay was performed and the inhibition of hypusine biosynthesis was determined by GC-MS. All tested compounds proved to be active in this assay and MMV665805 exhibited the strongest inhibitory effect. Notably, the results were in accordance with the preliminary quantum-mechanical calculations suggesting the strongest iron complexation capacity for MMV665805. This compound might be a useful tool as well as a novel lead structure for inhibitors of P. falciparum DOHH. [ABSTRACT FROM AUTHOR]

In the present study, we aimed to investigate plasma levels of peroxiredoxin 2 (Prx2) and thioredoxin 1 (Trx1), and the activity of thioredoxin reductase (TrxR), in thalassemia major (TM) patients living in the Antalya region, Turkey. The patients were divided into three groups, according to chelators - the deferoxamine group (DFO, n = 20), the deferasirox group (DFX, n = 20), and the deferiprone group (DFP, n = 20), to compare any possible effect of chelators on antioxidative and oxidative stress parameters. A control group ( n = 20) was selected from healthy volunteers. The activities of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and TrxR, as well as the concentrations of Prx2, Trx1, glucose-6-phosphate dehydrogenase (G-6-PD), reduced glutathione (GSH), hydrogen peroxide (H2O2), and malondialdehyde (MDA) were measured in the plasma samples of TM patients and the controls. The activity of CAT and the levels of H2O2 and MDA in the TM patients were significantly higher than those in the controls, while the levels of GPx, Trx1, TrxR, and GSH were lower. The concentrations of ferritin, GSH, H2O2, and MDA, as well as the activities of GR, CAT and TrxR, showed significant differences among the chelator groups. Although TrxR activity showed an increase in TM patients due to an elevated iron overload, both TrxR activity and Trx1 level were lower in the patient groups compared with the cases in the control group. As a result, because Trx1 level and TrxR activity were measured at a low level in the patients, increasing the levels of Trx1 and TrxR in TM patients will be a target of future treatment. [ABSTRACT FROM AUTHOR]

Mucormycosis is a rare fungal infection mainly affecting immunocompromised patients. Recently, an alarming rise in cases of mucormycosis was observed in patients undergoing COVID-19 treatment. Commonly, this fungal infection is caused by Rhizopus spp., Mucor spp., and Lichtheimia spp., although the genera of other Mucorales such as Saksenaea, Rhizomucor , Cunninghamella , and Apophysomyces may also be involved. A number of factors such as high concentration of zinc, iron and hypoxia induced acidosis promote the growth of fungi, thereby increasing the risk of mucormycosis multiple folds. Iron chelators (deferasirox and deferiprone) and zinc chelators (clioquinol, phenanthroline and N,N,N′,N′ -tetrakis-(2-pyridylmethyl)ethane-1,2-diamine) have been reported to inhibit the growth of fungi in a number of in vitro and animal studies. Correction of metabolic acidosis by administration of bicarbonate or glycine reduces the susceptibility of patients to the invasion by fungal species. However, these factors have largely been ignored while deciding the treatment strategy for mucormycosis and first line treatment for the management of mucormycosis continues to be the expensive lipid based formulation of amphotericin B. Treatment with isavuconazole which is proposed as the second choice is reported to be more cost effective. Therefore, it is proposed that a combination of antifungal agent (isavuconazole) with zinc and iron chelators (deferasirox and clioquinol respectively) along with alkalizer (glycine buffer) could be an effective and multi-target approach for the treatment of mucormycosis while being cost effective also. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, such as deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines HBL-2, Granta-519 and Jeko-1, with 50% inhibitory concentration (IC50) values of 7.99 ± 2.46 μM, 8.93 ± 2.25 μM and 31.86 ± 7.26 μM, respectively. Deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated down-regulation of phosphor-RB (Ser780) expression, which resulted in increasing levels of the E2F/RB complex and G1/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by down-regulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment. [ABSTRACT FROM AUTHOR]

Abstract: The O,S-donor analogues of maltol and deferiprone (DMHP), respectively, thiomaltol and DMHTP, have been investigated in solution for their iron-complexation ability, as well as their electrochemical behaviors, in the presence and absence of iron, aimed at the rationalization of their anti-oxidant activity, particularly, as hydroxyl radical scavengers and inhibitors of lipid peroxidation. The results were compared with those of the O,O-donor compounds and revealed that all the compounds are good iron chelators (pFe=14.1–20.2), but the O,S-donor ligands being somewhat weaker than the corresponding oxo-analogues. Also all the ligands appear to be able to prevent the redox cycling of iron, a relevant anti-oxidant activity, which seems to be primary due to their high capacity to form iron complexes which are not effective in promoting free radical reactions. This is a significant feature for the development of leading analogues as drug candidates with co-adjuvant roles in oxidative-stress dependent pathologies. [Copyright &y& Elsevier]

Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1). HIF-1 is a 'master switch' being an important physiological response mechanism, likely enhancing neuroprotective compensatory pathways involved in many physiological processes within the brain. This mini-review will discuss the multifunctional mechanisms of action of the drugs, M30 and HLA20 in preclinical models of neurodegeneration with a specific emphasis on their ability to activate the HIF-1 signal transduction pathway. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Excess “free” iron which occurs under certain physiological conditions participates in the formation of toxic reactive oxygen species via the “fenton” chemistry. The reactive oxygen species oxidize biomolecules and have been implicated in many oxidative stress-related diseases. However, the ideal therapy for treating iron overload problems in humans has not yet been developed. In this study, the phenolic molecules catechol, caffeic acid, and 2,5-dihydroxybenzoic acid were successfully coupled to glucosamine as model substrate in a 1:1 ratio using laccase. Furthermore, coupling of these molecules onto chitosans of different sizes was demonstrated, resulting in decrease in –NH2 groups as quantified via derivatization. A concomitant increase in iron-chelating capacity from below 3% to up to 70% upon phenolic functionalization was measured for the chitosans based on reduced ferrozine/Fe2+ complex formation. Interesting these phenolic compounds seems to also participate as cross-linkers in producing characteristic microspheres. This work therefore opens-up new strategies aimed at developing a new generation of iron-chelating biomedical polymers. [Copyright &y& Elsevier]

The results of a meeting of physicians convening in Latin America to develop expert opinions on the diagnosis, monitoring and treatment of iron overload are as follows. An accurate diagnosis can be obtained by neonatal screening for haemoglobinopathies, especially sickle cell disease and the thalassaemias. Disease-specific registries are needed to demonstrate the extent of the problem to health authorities. Disparities in the quantity and quality of blood products must be addressed, and uniform transfusion guidelines are necessary. Serum ferritin level is a feasible marker for iron overload in the region, while magnetic resonance imaging assessment can improve the diagnosis and monitoring of cardiac and liver iron content. Medical specialists, including radiologists, pathologists and others, and health authorities, can help to implement these methods and provide adequate resources. The recently available oral deferasirox can be used to conveniently administer iron chelation to transfusional iron-overloaded patients. [ABSTRACT FROM AUTHOR]

Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to anticancer drugs and disease progression in metastases or local recurrence. These characteristics of cancer cells may be related to the specific properties of cancer stem cells (CSC). CSCs are involved in inhibiting cells' maturation, which is essential for maintaining their self-renewal capacity and pluripotency. They show increased expression of transcription factor proteins, which were defined as stemness-related markers. This group of proteins includes OCT4, SOX2, KLF4, Nanog, and SALL4. It has been noticed that the metabolism of cancer cells is changed, and the demand for iron is significantly increased. Iron chelators have been proven to have antitumor activity and influence the expression of stemness-related markers, thus reducing chemoresistance and the risk of tumor cell progression. This prompts further investigation of these agents as promising anticancer novel drugs. The article presents the characteristics of stemness markers and their influence on the development and course of neoplastic disease. Available iron chelators were also described, and their effects on cancer cells and expression of stemness-related markers were analyzed. [ABSTRACT FROM AUTHOR]

Patients with thalassemia encounter increased consumption of zinc (Zn) and copper (Cu) from chronic hemolysis and increased excretion from iron chelation. Iron-enriched diet restriction may result in low Zn and Cu intakes. Recent data on Zn and Cu status among Thai pediatric patients with thalassemia are lacking. This study aimed to identify frequencies and determine risk factors of Zn and Cu deficiencies among patients with thalassemia. Patients with transfusion-dependent thalassemia (TDT) receiving iron chelation ≥12 months and nonTDT (NTDT) aged 2–20 years were recruited. Serum Zn and Cu were measured. Dietary intakes were ascertained by interviews. A total of 209 patients (TDT = 126, NTDT = 83) were enrolled. Zn deficiency seemed to be associated with disease severity as median (IQR) Zn level of TDT was lower than that of NTDT [77 (69−85) vs. 80 (72−88) mcg/dL, p = 0.05 ], while higher frequency of Zn deficiency was identified in the former (24 % vs. 14 %). In TDT, Zn deficiency was associated with patients >10 years (OR 4.6; 95 %CI 1.1–6.4, p = 0.03), which likely resulted from combined low dietary Zn intake, prolonged exposures to hemolysis and iron chelators. Frequencies of Cu deficiency were similarly low in TDT and NTDT (8% and 7%) with comparable median (IQR) Cu levels of 103 (90−124) and 110 (92−132) mcg/dL, respectively (p = 0.13). Cu levels were inversely associated with age (r=-0.65 and r=-0.62 in TDT and NTDT, respectively; p < 0.001). Compared with younger patients, Zn and Cu deficiencies were more common among patients with thalassemia >10 years. Age was a major factor associated with both Zn and Cu deficiencies. [ABSTRACT FROM AUTHOR]

Abstract: Salicylaldehyde isonicotinoyl hydrazone (SIH) is an iron-chelating aromatic hydrazone with promising pharmacological properties. However, it suffers from relatively short biological half-life. Hence, two novel derivates of SIH, HAP-INH and HPP-INH were synthesized in order to overcome this pharmacokinetic drawback. The aim of the present study was to employ HPLC-DAD and HPLC–MS/MS methods to investigate the identity of the putative impurities of these newly prepared substances, which are being formed in aqueous environment. At first, it was shown that their retention times as well as UV spectra did not correspond to any expected synthetic precursor, by-product or degradation product. HPLC-DAD analysis confirmed purity of peaks and revealed close but not identical UV spectra of putative impurities and corresponding hydrazones. The subsequent HPLC–MS/MS analyses using ESI and the ion trap mass analyzer showed the identical molecular ions (in both modes) as well as their fragmentation, which implicated presence of geometric isomers. This suggestion was further supported by the NMR analyses. Since the Z/E isomers can have different biological activities, results of this study might be of great importance for further development of the aroylhydrazones as novel drug candidates as well as from the theoretical point of view. [Copyright &y& Elsevier]

Epidemiological studies and experimental data suggest iron involvement in atherosclerosis. The relation between iron and atherosclerosis is complex and remains contradictory. In thalassemia patients, non transferrin bound iron (NTBI) and free hemoglobin (Hb) are present in plasma and may accelerate atherogenesis, but its progression may be inhibited by iron chelators. The mechanism whereby iron may stimulate atherogenesis has been intensively investigated. Non transferrin bound iron and sera from subjects with hemochromatosis induced endothelial activation with expression of vascular adhesion molecules and endothelial inflammatory chemokines. Such events could be inhibited by iron chelators and oxygen radical scavengers with intracellular activity. Iron chelators may be effective in preventing vascular damage in patients with high concentrations of NTBI as found in thalassemia. [ABSTRACT FROM AUTHOR]

The cardioprotective effect of polyhydroxylated 1,4-naphthoquinones on the experimental model of myocardial ischemia-reperfusion has been demonstrated previously. In this study, using different models, such as bulk organic phase, liposomes and sarcoplasmic reticulum (SR) vesicles, we have shown the ability of naturally occurring polyhydroxynaphthoquinones, echinochrome (Ech), spinochromes C, D and E (SpC, SpD and SpE) to inhibit free-radical oxidation induced by heme iron (hemin) or by free iron ions (in ferrous/ascorbate system). The polyhydroxy-1,4-naphthoquinones (PHNQs) were more effective in inhibiting the phosphatidyl choline liposome peroxidation induced by ferrous/ascorbate than that induced by hemin. The iron chelating ability of PHNQs was determined spectrophotometrically. Prevention of the ferrous/ascorbate-induced leakage of calcium by Ech was demonstrated in isolated SR vesicles from rabbit skeletal muscle. The PHNQs displayed high scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. We concluded that iron chelation predominates in the overall antioxidant potential of the polyhydroxynaphthoquinones. [ABSTRACT FROM AUTHOR]

In this paper, we present the responses of the white-rot fungus Perenniporia medulla-panis to iron availability with regard to alterations in growth, expression of cellular proteins, Fe3+-reducing activity, and Fe3+ chelators production. Iron supplementation stimulated fungal growth but did not result in a significant increase in biomass production. Catechol and hydroxamate derivatives were produced mainly under iron deficiency, and their productions were repressed under iron supplementation conditions. Perenniporia medulla-panis showed several cellular proteins in the range of 10–90 kDa. Some of them showed negative iron-regulation. Iron-supplemented medium also repressed both cell surface and extracellular Fe3+-reducing activities; however, the highest cell surface activity was detected at the initial growth phase, whereas extracellular activity increased throughout the incubation period. No significant production of chelators and extracellular Fe3+-reducing activity were observed within the initial growth phase, suggesting that the reduction of Fe3+ to Fe2+ is performed by ferrireductases. [ABSTRACT FROM AUTHOR]

Abstract: The suitability of the Fenton process for the remediation of soil and groundwater is limited by the necessity to acidify the reaction medium. This study examines the applicability of humic acid (HA) as an iron chelator in a modified Fenton system with the aim of extending the optimum pH range for this process towards neutral conditions. Addition of HA at a concentration of 50–100mgL−1 greatly enhances the rate of oxidation of organic compounds in a catalytic Fenton system in the range of pH 5–7. Similar rates at pH 5 in the presence of HA can be achieved as at pH 3 for a typical Fenton process in the absence of HA (k′=9×10−3 min−1 for benzene degradation at ). A comparison of the relative reactivities of various model compounds supported the hypothesis that OH are the main reactive species in the HA-modified Fenton system. In contrast, however, another type of chelated Fe-catalyst (Fe-TAML) proved to be more selective than expected for OH. A long-term study revealed that the HA itself is oxidized and thereby loses its ability to enhance the degradation of the pollutant molecules. Therefore, the HA-modified Fenton system is effective for degrading pollutants which are at least as reactive towards OH as the HA itself, such as BTEX, phenols or PAHs. The results obtained indicate that the HA-modified Fenton system is also applicable for compounds with a high sorption tendency towards HA. [Copyright &y& Elsevier]

Abstract: Ataxia-telangiectasia (A-T) is characterized by ataxia, genomic instability, and increased cancer incidence. Previously, iron chelator concentrations which suppressed normal cell colony formation increased A-T cell colony formation. Similarly, iron chelators preferentially increased A-T cell colony formation following peroxide exposure compared to normal cells. Last, A-T cells exhibited increased short-term sensitivity to labile iron exposure compared to normal cells, an event corrected by recombinant ATM (rATM) expression. Since chromosomal damage is important in A-T pathology and iron chelators exert beneficial effects on A-T cells, we hypothesized that iron chelators would reduce A-T cell chromosomal breaks. We treated A-T, normal, and A-T cells expressing rATM with labile iron, iron chelators, antioxidants, and t-butyl hydroperoxide, and examined chromosomal breaks and ATM activation. Additionally, the effect of ATM-deficiency on transferrin receptor (TfR) expression and TfR activity blockage in A-T and syngeneic A-T cells expressing rATM was examined. We report that (1) iron chelators and iron-free media reduce spontaneous and t-butyl hydroperoxide-induced chromosomal breaks in A-T, but not normal, or A-T cells expressing rATM; (2) labile iron exposure induces A-T cell chromosomal breaks, an event lessened with rATM expression; (3) desferal, labile iron, and copper activate ATM; (4) A-T cell TfR expression is lowered with rATM expression and (5) blocking TfR activity with anti-TfR antibodies increases A-T cell colony formation, while lowering chromosomal breaks. ATM therefore functions in iron responses and the maintenance of genomic stability following labile iron exposure. [Copyright &y& Elsevier]

Abstract: Chelator-mediated Fenton reactions (CMFRs) were used to decolorize a biodegradable-resistant polymeric dye (Poly R-478). Screening of different iron chelators was performed on Fe3+-reduction activity. All chelators showed Fe3+-reduction activity over a wide range of pH (2–7) and each mol of catecholate chelators (3,4-dihydroxiphenilacetic acid—DOPAC and 2,3-dihydroxibenzoic acid—DHBA) reduced about 5–6moles of Fe3+ whereas hydroxamate chelators (acetohydroxamic acid—AHA and desferrioxamine B—DFB) reduced Fe3+ stoichiometrically. The most effective decolorization of Poly R-478 was achieved by CMFR using catecholate chelators. In addition, a 24 factorial design was performed with the aim of evaluating the effects of the variables considered in this study (pH, [DOPAC], [Fe3+] and [H2O2]) and optimizing the dye decolorization, using response surface methodology. Statistical analysis of results showed that, in the range studied, except for Fe3+, all variables have a significant effect on dye decolorization. A second-order model is proposed to represent the Poly R-478 decolorization. At optimum conditions, complete decolorization of the dye (degradation of the chromophoric group) and also complete chemical degradation of the dye was observed. [Copyright &y& Elsevier]

Deferiprone (L1), and appropriate combinations with deferoxamine (DFO), can be used effectively for the treatment of thalassemia and other transfusional iron loading conditions. A number of experimental iron chelators such as deferasirox or IGL670 or Exjade (4-(3,5-bis (2-hydroxyphenyl)-1, 2, 4-triazol-1-yl)-benzoic acid), deferitrin (4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid- 4-one or L1NAll and starch DFO polymers, are under clinical evaluation. ICL670 is the most advanced in development and appears to be effective in reducing liver iron in some patients but is overall ineffective in causing negative iron balance. It is also suspected that it is not effective in cardiac iron removal. Combination therapies using L1, DFO and new iron chelating drugs may cause higher efficacy and lower toxicity by comparison to monotherapies. However, several limitations including the high cost of the new chelating drugs may not facilitate the availability of these new treatments to the vast majority of thalassemia patients, most of whom live in developing countries. [ABSTRACT FROM AUTHOR]

Our laboratories have prepared a novel class of iron (Fe) chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. This article will review the iron chelation efficacy of this series of chelators, both in cell culture and in animal models. Several PCIH analogs were shown to be effective at inducing iron mobilization and preventing iron uptake from the iron-transport protein, transferrin. Moreover, several of these ligands were effective at permeating the mitochondrion and inducing iron release. Studies in mice demonstrated that the PCIH analog, PCTH, was orally active and well tolerated by mice at doses ranging from 50 to 100 mg kg -1 , twice daily (b.d.). A dose-dependent increase in fecal 59 Fe excretion was observed in the PCTH-treated group. This level of iron excretion was similar to that found for the orally effective chelators, pyridoxal isonicotinoyl hydrazone (PIH) and deferiprone (L1). The PCIH group of ligands clearly has the potential for the treatment of ß-thalassemia (thal) and Friedreich's Ataxia (FA). [ABSTRACT FROM AUTHOR]

It is now generally accepted that it is not possible to design iron(III)-selective hexadentate chelators with high oral bioavailability. In order to achieve suitable levels of oral activity for the treatment of systemic iron overload either tridentate or bidentate molecules need to be investigated. There are a number of such molecules in clinical practice, including hydroxypyridin-4-ones, desferrithiocin analogues and bis-hydroxyphenyltriazoles. The underlying chemistry of each group is described, together with an indication of the distribution properties, redox cycling activity, and iron scavenging activity. [ABSTRACT FROM AUTHOR]

Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson’s disease, Alzheimer’s disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in rats and mice. However, their action on monoamine oxidase (MAO) A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and animal models of Parkinson’s disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl, U74500A and U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B. Their IC50 ranged from 10-3?M to 10-6?M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) were time dependent and irreversible. Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were fully reversible by enzyme dilution experiments. Both Fe2+ and Fe3+ reverse the MAO-A and B inhibition induced by the latter chelators, but not those initiated by 21-amino steroids. The data infer that either the inhibition of MAO by 21-amino steroids is either the resultant of their conversion to an irreversible covalently bound ligand or that the iron chelation moiety and MAO inhibitory activity in these compounds are not mutually shared. The results suggest that bifunctional brain penetrable drugs with iron chelating property and MAO inhibitory activity in could be the most feasible approach for neuroprotection in neurodegenerative diseases. Such drug would prevent participation of elevated iron in oxidative stress and formation of reactive hydroxyl radical, via its interaction with H2O2 (Fenton chemistry), generated as a consequence MAO and other oxidative enzyme reactions to generative cytotoxic reactive hydroxyl radical. We have now developed several of these compounds with neuroprotective, MAO inhibitory and iron chelating properties from our prototype iron chelators, VK-28 possessing propargylamine moiety of our anti-parkinson drug, rasagiline. [ABSTRACT FROM AUTHOR]

The method of synthesizing acyclonucleoside iron chelators is both convenient and cost effective compared to that of synthesizing ribonucleoside iron chelators. The X-ray crystal structural analysis shows that the 2-hydroxyethoxymethyl group does not affect the geometry of the iron chelating sites. Therefore, the iron binding and removal properties of the acyclonucleoside iron chelators should remain similar to the ribonucleoside iron chelators, which is confirmed by the titration and competition reaction of the acyclonucleoside chelators with iron and ferritin, respectively. The acyclonucleoside iron chelators are more lipophilic with measured n-octanol and Tris buffer distribution coefficients than ribonucleoside iron chelators. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that iron (Fe) and other metals play a role in a number of neurodegenerative diseases including Friedreich's ataxia, Alzheimer's disease, Huntington's disease, and Parkinson's disease, In this review, the role of Fe and other metals in the pathology of these conditions is assessed and the potential of Fe chelators for treatment is discussed. Lipophilic chelators have been designed that may be capable of crossing the blood-brain barrier, a property lacking in desferrioxamine (DFO), a chelator in widespread clinical use. A far less commonly used chelator, clioquinol, has already shown activity in vivo in animal models and also in Alzheimer's disease patients. Considering that there is no effective treatment for many neurological diseases, the therapeutic use of lipophilic Fe chelators remains a potential strategy that requires investigation. In particular, we discuss the development of several series of aroylhydrazone chelators that could have high potential in the treatment of these diseases. [ABSTRACT FROM AUTHOR]

Two types of iron chelators, desferrioxamine (DFO) and 2,2′-bipyridyl (BIP), selected for their differential binding properties, permeability and stoechiometry, were tested for their ability to inhibit the in vitro proliferation of the carpet shell clam parasite Perkinsus atlanticus. A tetrazolium-based assay was used to determine the effect of the drugs on cell proliferation. Both chelators were able to inhibit P. atlanticus proliferation in a dose-dependent manner, the 50% inhibitory concentration were 14 and 24 μM for DFO and BIP, respectively, in a 72 h test. This effect was reversed by co-addition of iron, confirming that this activity is due to the sequestration of iron. These results indicate a high degree of susceptibility of the protozoan parasite to chelator-induced iron deprivation. However, this effect was reversible upon removal of the drugs, indicating that the action of both chelators was cytostatic. For the range of concentrations tested the combined drug effects was not significantly higher than the additive effect of the individual drugs. [Copyright &y& Elsevier]

β-Thalassaemia is an inherited blood disorder which through repeated blood transfusions and enhanced iron uptake from the gastrointestinal tract, results in marked iron overload. Untreated, the iron accumulation results in the dysfunction of vital organs such as the heart and liver. At present, the most effective treatment for β-thalassaemia is the use of the iron chelator, desferrioxamine, which is expensive, orally inactive and requires long subcutaneous infusions. In this concise review, we will focus on novel chelators which show therapeutic potential to replace desferrioxamine. Furthermore, we will discuss the potential of combined iron chelation therapy and the principle that, in the future, the use of more than just one chelator may be beneficial in tailoring individual iron chelation regimens. [Copyright &y& Elsevier]