Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death

Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
Cell (Impact Factor: 32.24). 05/2012; 149(5):1060-72. DOI: 10.1016/j.cell.2012.03.042
Source: PubMed


Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.


Available from: Darpan Patel, Mar 30, 2014
    • "Ferroptosis may also occur by inhibition of glutathione peroxidase 4 (GPX4). Erasin, an oncogenic RAS-selective lethal compound, as well as the kinase inhibitor sorafenib have been identified to inhibit the cysteine–glutamate antiporter complex x c − and to induce irondependent , oxidative cell death (Dixon et al. 2012, 2014). Ferrostatin- 1 and deferoxamine are iron-depleting agents that inhibit ferroptosis (Louandre et al. 2013; Skouta et al. 2014). "
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    ABSTRACT: Background Apoptosis and other forms of cell death have been intensively investigated in the past years to explain the mode of action of synthetic anticancer drugs and natural products. Recently, a new form of cell death emerged, which was termed ferroptosis, because it depends on intracellular iron. Here, the role of genes involved in iron metabolism and homeostasis for the cytotoxicity of ten artemisinin derivatives have been systematically investigated. Material and methods Log10IC50 values of 10 artemisinin derivatives (artesunate, artemether, arteether, artenimol, artemisitene, arteanuin B, another monomeric artemisinin derivative and three artemisinin dimer molecules) were correlated to the microarray-based mRNA expression of 30 iron-related genes in 60 cell lines of the National Cancer Institute (NCI, USA) as determined in 218 different microarray hybridization experiments. The effect of desferoxamine and ferrostatin-1 on the cytotoxicity of artenimol of CCRF-CEM cells was determined by resazurin assays. The mRNA expression of TFRC was exemplarily validated by immunohistochemical detection of transferrin receptor protein expression. Results The mRNA expression of 20 genes represented by 59 different cDNA clones significantly correlated to the log10IC50 values for the artemisinins, including genes encoding transferrin (TF), transferrin receptors 1 and 2 (TFRC, TFR2), cerulopasmin (CP), lactoferrin (LTF) and others. The ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine led to a significantly reduced cytotoxicity of artenimol, indicating ferroptosis as cell death mode. Conclusion The numerous iron-related genes, whose expression correlated with the response to artemisinin derivatives speak in factor for the relevance of iron for the cytotoxic activity of these compounds. Treatment with ferroptosis-inducing agents such as artemisinin derivatives represents an attractive strategy for cancer therapy. Pre-therapeutic determination of iron-related genes may indicate tumor sensitivity to artemisinins. Ferroptosis induced by artemisinin-type drugs deserve further investigation for individualized tumor therapy.
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    • "Instead, sulfasalazine is an inhibitor of system x c À , the cystine-glutamate antiporter (Dixon et al., 2014), required for the biosynthesis of glutathione (GSH). Thus sulfasalazine inactivates enzymes that rely on reduced glutathione (GSH) as a cofactor, including glutathione peroxidase 4 (GPX4) (Dixon et al., 2012; Yang et al., 2014), leading to toxic accumulation of lipid reactive oxygen species (ROS). We thus tested whether altretamine may also modulate the system x c À -GPX4 pathway. "
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    • "An interesting hypothesis is that this activation might arise from direct phosphorylation of Caspase 3 or Caspase 6 by MST3 in mice and humans, respectively. Cystine glutamate transporter/Slc7a11, a transporter associated with glutamate toxicity in neurons, a putative substrate of MST3, is active in both neurons and glia (Bridges et al., 2012; Dixon et al., 2012; Jackman et al., 2012). Finally, the identification of eukaryotic elongation factor 1a as a putative MST3 target has implications in translational regulation. "
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