Ferroptosis - Importance and Potential Effects in Hematological Malignancies
Gabriel Ignacio Aranalde1, 2, * 1 Internal Medicine Service, âDr. Clemente Ălvarezâ Emergency Hospital, Rosario, Santa Fe. Argentina
2 Department of Physiological Sciences, National University of Rosario, Santa Fe, Argentina
Abstract
Ferroptosis is a recently identified form of non-apoptotic regulated cell death with distinct properties and several functions involved in physical conditions or various diseases. It has been related to the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's and Parkinson's diseases), carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration.
This entity is characterised by an iron-dependent accumulation of lipid peroxides, and it can be induced by experimental compounds and clinical drugs in cancer cells as well as certain normal cells. Some of the inductors are erastin, Ras-selective lethal small molecules (RSL3 and RSL5), buthionine sulfoximine, acetaminophen, ferroptosis-inducing agents, lanperisone, sulfasalazine, sorafenib, and artesunate.
Induction of ferroptosis by drugs has been shown to inhibit cancer cell growth, both in Ras-dependent and Ras-independent forms. This fact suggests that cancer cells display genetic heterogeneity in the timing of the ferroptosis response.
Malignant haematological entities have been subject to a wide variety of available treatments. However, the development of resistance to chemotherapeutic agents represents one of the biggest obstacles in the effectiveness of the treatment of some haematological neoplasms such as acute myeloid leukaemia. Ferroptosis has the potential to modify the course of treatment, and hence the prognosis, not only of acute myeloid leukaemia but also of diffuse large B-cell lymphoma, T-lymph coelom and myeloma.
An improved understanding of the role of ferroptosis in cancer and injury-associated diseases will create a new opportunity for diagnosis and therapeutic intervention.
Keywords: Apoptosis, Autophagy, Cancers, Ferroptosis, GPX4.
* Corresponding author Gabriel Ignacio Aranalde: Internal Medicine Service, âDr. Clemente Ălvarezâ Emergency Hospital. Rosario. Santa Fe. Argentina and Department of Physiological Sciences, National University of Rosario. Santa Fe. Argentina; E-mail: [email protected] INTRODUCTION
Ferroptosis, first described by Dixon in 2012, is a new form of programmed cell death which was only recently acknowledged [1]. Its main mechanism is due to insufficient antioxidant protection of cell lipid membranes which are usually subject to peroxidation [2, 3]. Contrary to other forms of programmed cell death, ferroptosis is controlled by glutathione peroxidase 4 (GPX4) and associated to a series of genes such as iron-responsive element-binding protein 2, citrate synthase, ribosomal protein L8, ATP synthase, H+ transporting and mitochondrial Fo complex subunit C3 (subunit 9) [3]. Some of the processes involved in ferroptosis are the activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter. Such processes are ultimately associated with the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism, which increase cell membranes permeability [2].
Ferroptosis is typically characterised by the following morpho-cytological changes: smaller mitochondrion with a condensed density of the mitochondrial membrane, mitochondrial cristae reduction or vanishing and outer mitochondrial membrane rupture [4].
Misregulated ferroptosis has been clinically related to multiple physiological processes and metabolic disorders with homeostasis disruption. Ferroptosis is gradually being accepted as a physiologically adaptative process for the control of malignant cell proliferation. Its primary importance lies in the removal of cells that are in an environment depleted of nutrients, or damaged by infection, stress or both [5]. It has been clinically related to specific physiological processes such as T-cell immunity and multiple neoplastic clinical entities (haematological malignancies, renal cell carcinoma, hepatocellular carcinoma, ovarian cancer, prostate adenocarcinoma, breast cancer, lung cancer, colorectal cancer, gastric cancer, and rhabdomyosarcoma) [4, 6] and non-neoplastic clinical entities (neurotoxicity, neurodegenerative diseases, hepatic and heart ischemia/reperfusion injury) [7, 8]. The distinctive metabolic features of ferroptosis vary according to the different types of cancer [4].
MAIN FEATURES OF DIFFERENT PROGRAMMED CELL DEATH PROCESSES
Introduction
Programmed cell death is an essential process not only for the development of living beings but also for persistent homeostasis. Cellular death provides the opportunity of controlling the quantity and quality of cells in the body [9].
For hundreds of years, even before the concept 'cell' was fully comprehended, different concepts related to cellular death had been postulated. Already in the second century BC, Galeno mentions certain ephemeral structures, whose disappearance seemed programmed from birth, a concept that was opposed to the observation of clearly abnormal development of gangrenous tissue due to severe damage. It was only in 1972, that Kerr, Willie and Currie used the terms necrosis and apoptosis to unify both concepts and, in turn, differentiate accidental cell death from regulated cell death [10].
At present, the Nomenclature Committee on Cell Death (NCCD) sets up a differentiation between programmed and accidental cell death. The latter is provoked by a variety of physical, chemical and mechanical stimuli, and it cannot be altered by molecular changes [11].
Programmed cell death, unlike accidental cell death, is a process represented by a series of steps, each of them involving the action of different genetically coded molecules and tightly integrated with other biological processes. It can be regulated both pharmacologically and genetically and, therefore, it is under the control of specific intrinsic cell mechanisms. The NCCD defines programmed cell death as a subset of regulated cell death that is predestined to occur in normal physiological settings [11].
The different types of programmed cell death may coincide in the use of one or more of such molecules; and these molecules, in turn, can be physiologically, pharmacologically or genetically regulated [4].
Due to the importance of this process, each cell produces its self-destruction tools from the moment of its birth. Such production is controlled by each cell's capabilities to receive, process and produce signals that activate or inhibit some of the elements of the lethal machinery. With the enormous cell heterogeneity of superior organisms, the above implies numerous pathways a cell may use in order to self-destruct. Those pathways are incredibly complex and m...