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      Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models

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          Abstract

          Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.

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          Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.

          Sonam Dolma, Stephen Lessnick, William C. Hahn … (2003)
          We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase 1 and sensitized cells to a nonapoptotic cell death process initiated by erastin.
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            Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.

            Tomoyoshi Soga, Richard Baran, Makoto Suematsu … (2006)
            Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. We globally detected 1,859 peaks in mouse liver extracts and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with gamma-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Our method can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers.
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              Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress.

              Timothy H. Murphy, Masaomi Miyamoto, Antonio Sastre … (1989)
              Glutamate binds to both excitatory neurotransmitter binding sites and a Cl(-)-dependent, quisqualate- and cystine-inhibited transport site on brain neurons. The neuroblastoma-primary retina hybrid cells (N18-RE-105) are susceptible to glutamate-induced cytotoxicity. The Cl(-)-dependent transport site to which glutamate and quisqualate (but not kainate or NMDA) bind has a higher affinity for cystine than for glutamate. Lowering cystine concentrations in the cell culture medium results in cytotoxicity similar to that induced by glutamate addition in its morphology, kinetics, and Ca2+ dependence. Glutamate-induced cytotoxicity is directly proportional to its ability to inhibit cystine uptake. Exposure to glutamate (or lowered cystine) causes a decrease in glutathione levels and an accumulation of intracellular peroxides. Like N18-RE-105 cells, primary rat hippocampal neurons (but not glia) in culture degenerate in medium with lowered cystine concentration. Thus, glutamate-induced cytotoxicity in N18-RE-105 cells is due to inhibition of cystine uptake, resulting in lowered glutathione levels leading to oxidative stress and cell death.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Am Chem Soc
                Journal ID (iso-abbrev): J. Am. Chem. Soc
                Journal ID (publisher-id): ja
                Journal ID (coden): jacsat
                Title: Journal of the American Chemical Society
                Publisher: American Chemical Society
                ISSN (Print): 0002-7863
                ISSN (Electronic): 1520-5126
                Publication date PMC-release: 04 March 2015
                Publication date (Electronic): 04 March 2014
                Publication date (Print): 26 March 2014
                Volume: 136
                Issue: 12
                Pages: 4551-4556
                Affiliations
                [† ]Department of Biological Sciences, Columbia University , 550 West 120th Street Northwest Corner Building, MC 4846 New York, New York 10027, United States
                [‡ ]Department of Chemistry, Columbia University , New York, New York 10027, United States
                [§ ]Department of Neurology, Children’s Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States
                [∥ ]Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center , Durham, North Carolina 27704, United States
                [⊥ ]Department of Internal Medicine/Nephrology, University of Michigan , Ann Arbor, Michigan 48109, United States
                [# ]Clinic for Nephrology and Hypertension, Christian-Albrechts-University , Kiel 24105, Germany
                [6] ⊗Department of Systems Biology and Howard Hughes Medical Institute, Columbia University , New York, New York 10027, United States
                Author notes
                Article
                DOI: 10.1021/ja411006a
                PMC ID: 3985476
                PubMed ID: 24592866
                SO-VID: 36b6f118-ce76-4d48-8a71-e51e7c65dd45
                Copyright © Copyright © 2014 American Chemical Society
                History
                Date received : 06 November 2013
                Funding
                National Institutes of Health, United States
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 ja411006a
                document-id-new-14 ja-2013-11006a
                ccc-price

                ScienceOpen disciplines: Chemistry
                Data availability:
                ScienceOpen disciplines: Chemistry

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