title: Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death.
abstract: Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkat cells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven proved to possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotective dibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydrogen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell death while caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide activated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase (JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotection was confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effect is not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective compounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independent of poly(ADP-ribose) polymerase inhibition.
authors.affiliation: Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Hegedűs
authors.forename: Petra
authors.initials: P
authors.lastname: Lakatos
authors.forename: Attila
authors.initials: A
authors.lastname: Kiss-Szikszai
authors.forename: Tamás
authors.initials: T
authors.lastname: Patonay
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Gergely
authors.forename: Andrea
authors.initials: A
authors.lastname: Gregus
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Éva
authors.initials: É
authors.lastname: Szabó
authors.forename: László
authors.initials: L
authors.lastname: Virág
mesh_terms: D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D047188:Chalcones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C061481:dibenzoylmethane; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases