The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

Pieter Spincemaille, Duc Hung Pham, Gursimran Chandhok, Jef Verbeek, Andree Zibert, Louis Libbrecht, Hartmut Schmidt, Camila V. Esguerra, Peter A.M. de Witte, Bruno P.A. Cammue, David Cassiman, Karin Thevissen

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9 Citations (Scopus)

Abstract

Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7BH1069Q, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment.

Original languageEnglish
Pages (from-to)345-351
Number of pages7
JournalToxicology and Applied Pharmacology
Volume280
Issue number2
DOIs
Publication statusPublished - 15 Oct 2014
Externally publishedYes

Keywords

  • Copper
  • Hepatotoxicity
  • OSIP108
  • Wilson disease
  • Zebrafish

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