Fiche publication
Date publication
août 2014
Journal
Biochimica et biophysica acta
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth
Tous les auteurs :
Jortzik E, Farhadi M, Ahmadi R, Tóth K, Lohr J, Helmke BM, Kehr S, Unterberg A, Ott I, Gust R, Deborde V, Davioud-Charvet E, Réau R, Becker K, Herold-Mende C
Lien Pubmed
Résumé
Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-β-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430μM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
Mots clés
Animals, Apoptosis, drug effects, Brain Neoplasms, drug therapy, Cell Movement, drug effects, Cell Proliferation, drug effects, Enzyme Inhibitors, chemical synthesis, Glioma, drug therapy, Glutathione, metabolism, Glutathione Reductase, antagonists & inhibitors, Gold, chemistry, Humans, Male, Organophosphorus Compounds, chemical synthesis, Rats, Rats, Wistar, Thioredoxin-Disulfide Reductase, antagonists & inhibitors, Tumor Cells, Cultured
Référence
Biochim. Biophys. Acta. 2014 Aug;1844(8):1415-26
