Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

Kontoghiorghes, George J.

doi:10.3390/ijms23126735

Cited by 11 publications

(5 citation statements)

References 188 publications

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“…The importance of iron in cellular function processes including cell death has been recently highlighted by the discovery of ferroptosis, which is a newly described programmed cell death based on oxytosis, which is caused by free radicals arising from iron catalysis and involving transcription and many other factors [ 68 , 69 , 70 ]. Ferroptosis has been implicated as an important process not only in health but also in diseases, including cancer, COVID-19, hematologic, neurodegenerative, cardiac, kidney, infectious diseases, and many others [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Ferroptosis is morphologically, biochemically, and genetically distinct from apoptotic and necrotic cell death and is mainly characterized by the accumulation of lipid peroxides on cell membranes, decrease in glutathione production, inhibition of glutathione peroxidase (GPX4) activity, an increase in intracellular iron, the sustainable production of increased free radical reactions caused mainly by labile but also other forms of iron, ferritinophagy, and an iron-dependent autophagic cell death program ( Figure 2 ) [ 68 , 69 , 70 , 81 , 82 , 83 , 84 , 85 ].…”

Section: Iron Metabolism and Iron Toxicity In Chronically Transfused ...mentioning

confidence: 99%

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Kontoghiorghes

2023

IJMS

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Iron is essential for all organisms and cells. Diseases of iron imbalance affect billions of patients, including those with iron overload and other forms of iron toxicity. Excess iron load is an adverse prognostic factor for all diseases and can cause serious organ damage and fatalities following chronic red blood cell transfusions in patients of many conditions, including hemoglobinopathies, myelodyspasia, and hematopoietic stem cell transplantation. Similar toxicity of excess body iron load but at a slower rate of disease progression is found in idiopathic haemochromatosis patients. Excess iron deposition in different regions of the brain with suspected toxicity has been identified by MRI T2* and similar methods in many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Based on its role as the major biological catalyst of free radical reactions and the Fenton reaction, iron has also been implicated in all diseases associated with free radical pathology and tissue damage. Furthermore, the recent discovery of ferroptosis, which is a cell death program based on free radical generation by iron and cell membrane lipid oxidation, sparked thousands of investigations and the association of iron with cardiac, kidney, liver, and many other diseases, including cancer and infections. The toxicity implications of iron in a labile, non-protein bound form and its complexes with dietary molecules such as vitamin C and drugs such as doxorubicin and other xenobiotic molecules in relation to carcinogenesis and other forms of toxicity are also discussed. In each case and form of iron toxicity, the mechanistic insights, diagnostic criteria, and molecular interactions are essential for the design of new and effective therapeutic interventions and of future targeted therapeutic strategies. In particular, this approach has been successful for the treatment of most iron loading conditions and especially for the transition of thalassemia from a fatal to a chronic disease due to new therapeutic protocols resulting in the complete elimination of iron overload and of iron toxicity.

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Section: Iron Metabolism and Iron Toxicity In Chronically Transfused ...mentioning

confidence: 99%

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Kontoghiorghes

2023

IJMS

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“…Deferiprone can permeate the blood-brain barrier, and it has also been shown to reduce labile iron in the retina [115] , without causing retinal toxicity in mice [118] . The activity of HIF prolylhydroxylases can be reduced and the antihypoxic response increased by removing or displacing iron, thus improving the hypoxic state in patients with COVID-19 [119] . Deferasirox Deferasirox, a tridentate chelator with high affinity for Fe 3+ , binds to iron in a 2:1 ratio to form a complex with a long half-life of about 8-16h.…”

Section: Iron Chelation Therapymentioning

confidence: 99%

Therapeutic potential of iron chelators in retinal vascular diseases

Li,

Luo,

Lyu

2023

Int J Ophthalmol

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Iron is one of the necessary metal elements in the human body. There are numerous factors that control the balance of iron metabolism, and its storage and transportation mechanisms are intricate. As one of the most energy-intensive tissues in the body, the retina is susceptible to iron imbalance. The occurrence of iron overload in the retina leads to the generation of a significant quantity of reactive oxygen species. This will aggravate local oxidative stress and inflammatory reactions and even lead to ferroptosis, eventually resulting in retinal dysfunction. The blood-retina-retinal barrier is eventually harmed by oxidative stress and elevated inflammation, which are characteristics of retinal vascular disorders. The pathophysiology of retinal vascular disorders may be significantly influenced by iron. Recently, iron-chelating agents have been found to have antioxidative and anti-inflammatory actions in addition to iron chelating. Therefore, iron neutralization is considered to be a new and potentially useful therapeutic strategy. This article reviews the iron overload in retinal vascular diseases and discusses the therapeutic potential of iron-chelating agents.

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“…The importance of iron in health and disease, and especially in cancer mechanisms, has been further highlighted by the recent discovery of ferroptosis, which is a form of oxytosis caused by free radicals arising from iron and involves transcription and many other factors [118]. In addition to cancer, ferroptosis is implicated in infectious, neurodegenerative, cardiac, kidney and many other diseases including COVID-19 [119][120][121][122][123][124]. There have been more than 2000 publications in the last 10 years describing many different aspects of the role of ferroptosis in cancer, with the annual number of citations and publications growing exponentially over the past decade [125].…”

Section: Ferroptosis the New Target In Cancer Therapies And The Role ...mentioning

confidence: 99%

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

Kontoghiorghes¹

2022

IJMS

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There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron–chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.

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Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

Cited by 11 publications

References 188 publications

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

Therapeutic potential of iron chelators in retinal vascular diseases

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

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