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

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

Toxicology and applied pharmacology (2014-08-20)
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
ABSTRACT

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. 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. OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B(H1069Q), 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. OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Copper(II) sulfate, anhydrous, powder, ≥99.99% trace metals basis
Sigma-Aldrich
Copper(II) sulfate, ReagentPlus®, ≥99%
Sigma-Aldrich
Copper(II) chloride, powder, 99%
Sigma-Aldrich
Copper(II) chloride, 97%
Sigma-Aldrich
Copper(II) chloride, anhydrous, powder, ≥99.995% trace metals basis
Sigma-Aldrich
Copper(II) chloride, 99.999% trace metals basis