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High-content screening identifies inhibitors of oxidative stress-induced parthanatos: cytoprotective and anti-inflammatory effects of ciclopirox.
Regdon, Zsolt; Demény, Máté A; Kovács, Katalin; Hajnády, Zoltán; Nagy-Pénzes, Máté; Bakondi, Edina; Kiss, Alexandra; Hegedus, Csaba; Virág, László.
Afiliación
  • Regdon Z; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Demény MA; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Kovács K; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Hajnády Z; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Nagy-Pénzes M; MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary.
  • Bakondi E; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Kiss A; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
  • Hegedus C; Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • Virág L; Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
Br J Pharmacol ; 178(5): 1095-1113, 2021 03.
Article en En | MEDLINE | ID: mdl-33332573
BACKGROUND AND PURPOSE: Excessive oxidative stress can induce PARP1-mediated programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos. EXPERIMENTAL APPROACH: A small library of 774 pharmacologically active compounds was screened in a Sytox Green uptake assay, which identified 20 hits that reduced hydrogen-peroxide-induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34. KEY RESULTS: Of these hits, two compounds, antifungal ciclopirox and dopamine receptor agonist apomorphine, inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H2 O2 production and suppressed DNA breakage. Since H2 O2 -induced damage is dependent on Fe2+ -catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that ciclopirox and, to a lesser extent, apomorphine act as iron chelators. We also show that the Fe2+ chelation and indirect PARP inhibitory effects of ciclopirox translate to anti-inflammatory actions as demonstrated in a mouse dermatitis model, where ciclopirox reduced ear swelling, inflammatory cell recruitment and poly(ADP-ribosyl)ation. CONCLUSION AND IMPLICATIONS: Our findings indicate that the antimycotic drug, ciclopirox, acts as an iron chelator and thus targets an early event in hydrogen-peroxide-induced parthanatos. Ciclopirox has the potential to be repurposed as a cytoprotective and anti-inflammatory agent.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parthanatos Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2021 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Parthanatos Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals Idioma: En Revista: Br J Pharmacol Año: 2021 Tipo del documento: Article País de afiliación: Hungria Pais de publicación: Reino Unido