A Synthetic Superoxide Dismutase/Catalase Mimetic (EUK-134) Inhibits Membrane-Damage-Induced Activation of Mitogen-Activated Protein Kinase Pathways and Reduces p53 Accumulation in Ultraviolet B-Exposed Primary Human Keratinocytes

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Abstract

Salen-manganese complexes exhibit powerful superoxide dismutase and catalase activity, with pharmacologic efficacy in several oxidative-stress- associated disease models. Ultraviolet (UV) B not only induces direct DNA damage, but also generates oxidative stress. EUK-134, a salen-manganese complex, might therefore confer a direct protection against UVB-induced oxidative stress and consequently alleviate UVB-damage-induced signal transduction. We investigated the effect of EUK-134 on the UVB-induced accumulation and stabilization of the p53 protein. p53 plays a central role in the UVB response, both as sensor of UVB damage and as a mediator of a protective response. Cells treated with EUK-134 before UVB irradiation showed a significantly lower accumulation of the p53 protein in a concentration-dependent fashion. Furthermore, EUK-134 severely reduced N-terminal phosphorylation of p53. The extracellular signal-regulated kinase ERK and the stress-activated kinases JNK and p38 have been implicated in the UVB-induced N-terminal phosphorylation and accumulation of p53. Pre-treatment with EUK-134 inhibited the UVB-induced activation of these mitogen-activated protein kinase (MAPK) pathways. We hypothesize that EUK-134, by direct protection of the membrane from UVB-induced oxidative damage, reduces oxidative stress induced MAPK signaling and consequently lowers the level of p53 induction. The protection conferred by EUK-134 resulted in a significant increase in cell survival following UVB irradiation.

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Decraene, D., Smaers, K., Gan, D., Mammone, T., Matsui, M., Maes, D., … Garmyn, M. (2004). A Synthetic Superoxide Dismutase/Catalase Mimetic (EUK-134) Inhibits Membrane-Damage-Induced Activation of Mitogen-Activated Protein Kinase Pathways and Reduces p53 Accumulation in Ultraviolet B-Exposed Primary Human Keratinocytes. Journal of Investigative Dermatology, 122(2), 484–491. https://doi.org/10.1046/j.0022-202X.2004.22215.x

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