-
Biometals : An International Journal on... Oct 2020Iron chelators have long been a target of interest as anticancer agents. Iron is an important cellular resource involved in cell replication, metabolism and growth. Iron... (Review)
Review
Iron chelators have long been a target of interest as anticancer agents. Iron is an important cellular resource involved in cell replication, metabolism and growth. Iron metabolism is modulated in cancer cells reflecting their increased replicative demands. Originally, iron chelators were first developed for use in iron overload disorders, however, their potential as anticancer agents has been gaining increasing interest. This is due, in part, to the downstream effects of iron depletion such as the inhibition of proliferation through ribonucleotide reductase activity. Additionally, some chelators form redox active metal complexes with iron resulting in the production of reactive oxygen species and oxidative stress. Newer synthetic iron chelators such as Deferasirox, Triapine and di-2-pyridylketone-4,4,-dimethyl-3-thiosemicrbazone (Dp44mt) have improved pharmacokinetic properties over the older chelator Deferoxamine. This review examines and discusses the various iron chelators that have been trialled for cancer therapy including both preclinical and clinical studies. The successes and shortcomings of each of the chelators and their use in combination therapies are highlighted and future potential in the cancer therapy world is considered.
Topics: Animals; Antineoplastic Agents; Humans; Iron Chelating Agents; Neoplasms
PubMed: 32757166
DOI: 10.1007/s10534-020-00243-3 -
The Journal of Biological Chemistry Jan 2020Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional...
Ferroptosis is an iron-dependent programmed cell death event, whose regulation and physiological significance remain to be elucidated. Analyzing transcriptional responses of mouse embryonic fibroblasts exposed to the ferroptosis inducer erastin, here we found that a set of genes related to oxidative stress protection is induced upon ferroptosis. We considered that up-regulation of these genes attenuates ferroptosis induction and found that the transcription factor BTB domain and CNC homolog 1 (BACH1), a regulator in heme and iron metabolism, promotes ferroptosis by repressing the transcription of a subset of the erastin-induced protective genes. We noted that these genes are involved in the synthesis of GSH or metabolism of intracellular labile iron and include (), (), (), (), and (). Ferroptosis has also been previously shown to induce cardiomyopathy, and here we observed that mice are more resistant to myocardial infarction than WT mice and that the severity of ischemic injury is decreased by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that BACH1 represses genes that combat labile iron-induced oxidative stress, and ferroptosis is stimulated at the transcriptional level by BACH1 upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. We propose that BACH1 controls the threshold of ferroptosis induction and may represent a therapeutic target for alleviating ferroptosis-related diseases, including myocardial infarction.
Topics: Amino Acid Transport System y+; Animals; Basic-Leucine Zipper Transcription Factors; Cation Transport Proteins; Cells, Cultured; Ferritins; Ferroptosis; Fibroblasts; Glutamate-Cysteine Ligase; Glutathione; Iron; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Oxidative Stress; Oxidoreductases; Transcriptional Activation
PubMed: 31740582
DOI: 10.1074/jbc.RA119.009548 -
Current Cancer Drug Targets 2021Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron...
BACKGROUND
Osteosarcoma is an aggressive bone tumor. It represents the principal cause of cancer-associated death in children. Considering the recent findings on the role of iron in cancer, iron chelation has been investigated for its antineoplastic properties in many tumors. Deferasirox is the most used iron chelator compound and in previous studies showed an anticancer effect in hematologic and solid malignancies. Eltrombopag is a Thrombopoietin receptor used in thrombocytopenia that also binds and mobilize iron. It demonstrated an effect on iron overload conditions and also in contrasting cancer cell proliferation.
OBJECTIVE
We analyzed the effects of deferasirox and eltrombopag in human osteosarcoma cells in an attempt to identify other therapeutic approaches for this tumor.
METHODS
We cultured and treated with deferasirox and Eltrombopag, alone and in combination, two human osteosarcoma cell lines, MG63 and 143B. After 72h exposure, we performed RTqPCR, Western Blotting, Iron Assay and cytofluorimetric assays to evaluate the effect on viability, apoptosis, cell cycle progression and ROS production.
RESULTS
The iron-chelating properties of the two compounds are also confirmed in osteosarcoma, but we did not observe any direct effect on tumor progression.
DISCUSSION
We tested deferasirox and eltrombopag, alone and in combination, in human osteosarcoma cells for the first time and demonstrated that their iron-chelating activity does not influence biochemical pathways related to cancer progression and maintenance.
CONCLUSION
Although further investigations on possible effects mediated by cells of the tumor microenvironment could be of great interest, in vitro iron chelation in osteosarcoma does not impair tumor progression.
Topics: Apoptosis; Benzoates; Bone Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deferasirox; Drug Therapy, Combination; Humans; Hydrazines; Iron Chelating Agents; Osteosarcoma; Pyrazoles; Treatment Outcome
PubMed: 33380300
DOI: 10.2174/1568009620666201230090531 -
Blood Oct 2020
Topics: Aged, 80 and over; Anemia, Sideroblastic; Arteriosclerosis; Biopsy; Blood Transfusion; Blood Vessels; Bone Marrow; Deferasirox; Female; Humans; Iron; Iron Overload; Metals, Heavy; Myelodysplastic-Myeloproliferative Diseases; Thrombocytosis; Transfusion Reaction; Treatment Failure
PubMed: 33091139
DOI: 10.1182/blood.2020007779 -
European Journal of Ophthalmology Apr 2024Deferasirox is the only iron chelator available in oral formulation and a rare cause of pigmentary retinopathy. We report the first case of multimodal imaging in an...
INTRODUCTION
Deferasirox is the only iron chelator available in oral formulation and a rare cause of pigmentary retinopathy. We report the first case of multimodal imaging in an adult with deferasirox retinopathy.
METHODS
Case report and literature review, with search terms including deferasirox retinopathy and deferasirox toxicity.
RESULTS
A 63-year-old man with end stage renal disease and transfusion-dependent anemia on deferasirox for one year presented with asymptomatic pigment epitheliopathy. Optical coherence tomography featured outer retinal and retinal pigment epithelial discontinuity corresponding to hypoautofluorescence on fundus autofluorescence and blocking on fluorescein angiography. Multifocal electroretinography revealed subtle reduction in all amplitudes.
CONCLUSIONS
Retinal examinations should be considered for patients requiring chronic administration of deferasirox.
PubMed: 38562036
DOI: 10.1177/11206721241245740 -
La Revue de Medecine Interne Dec 2023Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including... (Review)
Review
Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000μg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120μmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions.
Topics: Humans; Hemochromatosis; Hyperferritinemia; Iron Overload; Iron; Ferritins
PubMed: 37507250
DOI: 10.1016/j.revmed.2023.07.002 -
Journal of Toxicology 2022Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged.... (Review)
Review
Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.
PubMed: 35571382
DOI: 10.1155/2022/4911205 -
Current Pharmaceutical Biotechnology 2022Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in... (Review)
Review
Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in some organs including the liver, glands, brain, heart, gastrointestinal tract and lung. Iron chelation therapy could be considered an effective approach for removing excess iron. Deferoxamine, deferiprone and deferasirox are three common iron chelators in clinical practice but cause several side effects. In this context, the use of curcumin, a dietary phytochemical derived from turmeric, as a natural and safe antioxidant with iron-chelating activity may be a useful strategy for the management of iron overload. This review focuses on the deleterious effect of iron accumulation in different organs of the body as well as the therapeutic potential of curcumin against iron-induced toxicity.
Topics: Curcumin; Deferiprone; Deferoxamine; Humans; Iron; Iron Chelating Agents; Iron Overload; Pyridones
PubMed: 34521323
DOI: 10.2174/1389201022666210914122846 -
Indian Journal of Pediatrics Jan 2020Beta thalassemia major (TM) is the most frequent form of transfusion-dependent inherited anemia in India. The thalassemia syndromes exhibit enormous variability in... (Review)
Review
Beta thalassemia major (TM) is the most frequent form of transfusion-dependent inherited anemia in India. The thalassemia syndromes exhibit enormous variability in their genetic basis and phenotypic expression. The authors recommend that the diagnosis of TM or non-transfusion-dependent thalassemia (NTDT) should not be based on a one-time assessment. Many patients have a chronic anemia that is not severe enough to justify regular transfusions, but the clinical course can evolve with age. Continued observation may reveal that some patients who are considered NTDT will benefit from transfusions later in life. Clinical decision making can be influenced by the perceived difficulty in access to a safe blood supply and the cost of therapy. Here, authors present selected case scenarios that address common issues in the management of TM or NTDT. The recommendations are based on published evidence where available or on the authors' shared experience. Among the topics under discussion are deciding when to start regular transfusions, the role of hydroxyurea in TM, the procedure for blood administration, the use of deferasirox for chelation and monitoring of side effects, the role of splenectomy, and the prospects for gene therapy. In order to achieve an optimal outcome with blood transfusions and chelation therapy over the lifetime, it is essential to adhere to the current guidelines for the management of thalassemia.
Topics: Blood Transfusion; Chelation Therapy; Humans; Hydroxyurea; India; Splenectomy; Thalassemia; beta-Thalassemia
PubMed: 31620986
DOI: 10.1007/s12098-019-03065-5