Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death

Hegedűs, Csaba and Lakatos, Petra and Kiss, Attila and Patonay, Tamás and Gergely, Szabolcs Gábor and Gregus, Andrea and Bay, Péter and Haskó, György and Szabó, Éva and Virág, László (2013) Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death. PHARMACOLOGICAL RESEARCH, 72. pp. 25-34. ISSN 1043-6618

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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.

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