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

Abstract

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.

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

“…Both L1 and DFRA are orally active, whereas DF is orally inactive and has to be administered subcutaneously and sometimes intravenously to be effective (Figure 1). The iron-binding properties and effects of the iron-chelating drugs and a number of naturally occurring phytochelators such as mimosine and 2,3-dihydroxybenzoic acid or synthetic chelating drugs such as EDTA and DTPA have also been previously introduced and compared to the chelating drugs [62,66,80,81] (Figure 1). toxicity from the molecular, cellular and tissue level to clinical implications have been recently reviewed [81].…”

“…The iron-binding properties and effects of the iron-chelating drugs and a number of naturally occurring phytochelators such as mimosine and 2,3-dihydroxybenzoic acid or synthetic chelating drugs such as EDTA and DTPA have also been previously introduced and compared to the chelating drugs [62,66,80,81] (Figure 1). toxicity from the molecular, cellular and tissue level to clinical implications have been recently reviewed [81].…”

“…Iron chelation therapy can prevent iron overload toxicity and can substantially decrease the associated mortality and morbidity in TM and other categories of regularly RBC-transfused iron-loaded patients [81][82][83][119][120][121]. This goal can be achieved using effective chelating drug protocols, which can cause negative iron balance, where the amount of iron removed from the body is higher than the amount of iron accumulated by the intake of excess iron from RBC transfusions and also from increases in dietary iron absorption [122].…”

“…Many other categories of patients in addition to TM are affected by excess iron deposition (EID) and other forms of iron toxicity. The mechanistic insights in diseases related to EID and toxicity from the molecular, cellular and tissue level to clinical implications have been recently reviewed [81].…”

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

“…This signifies a notable advance in personalized oncology, directing focus towards unraveling cancer's complex molecular landscape through interventions focusing on iron and copper mechanisms in clinical settings [17,20]. Nonetheless, the utilization of iron and copper-induced cell death in cancer therapy introduces adverse effects on normal cellular function [21,22] and perturbs the equilibrium of adjacent T cells and macrophages, thereby bringing out the intricate interplay between metal-induced cytotoxicity and immune responses [23,24]. Through integrating molecular insights and detailed case studies and summarizing current knowledge with future perspectives, we elucidate the significance of iron and copper in cancer.…”