Authors: F Pajonk J Scholber B Fiebich
Publish Date: 2005/01/26
Volume: 55, Issue: 5, Pages: 439-446
Abstract
Hypericin is the presumed active moiety within Saint John’s wort Extracts of Saint John’s wort are widely used as an effective treatment for depression Available as “overthecounter” drugs they are frequently part of the selfmedication of patients undergoing radiation therapy for malignant diseases In addition to antidepressive properties hypericin has been shown to be able to induce apoptosis and radiosensitize tumor cells and to have antiinflammatory and phototoxic skin effects However the underlying mechanisms are not clear In this study we investigated possible inhibitory effects of hypericin on proteasome function and related pathways Extracts from U373 human glioma cells were incubated with different concentrations of hypericin Three proteasome activities were monitored using a fluorogenic peptide assay Activity of the transcription factor NFκB and protein levels of p65 p50 IκBα and caspase3 were investigated by EMSA and Western blotting respectively Hypericin caused a dosedependent and photoactivationindependent inhibition of proteasome function Hypericin treatment 625–50 μM inhibited NFκB caused accumulation of phosphorylated IκBα decreased p50 protein levels and induced cleavage of p65 protein in U373 cells These effects were observed in MCF7 cells only at higher concentrations of hypericin 125–50 μM Additionally inhibition of NFκB activity in U373 cells by hypericin was prevented by caspase inhibition Although hypericin clearly inhibits proteasome function its effect NFκB DNAbinding activity was not exclusively proteasomedependent The underlying mechanism might also involve caspase activation a consequence of proteasome inhibition
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