Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.
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.
Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
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Jortzik
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Germany.
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M
Farhadi
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Germany.
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Ahmadi
Division Biophysics of Macromolecules, German Cancer Research Center Heidelberg, Germany.
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Tóth
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Germany.
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Lohr
Institute of Pathology, Elbe Klinikum Stade, Germany; Department of General Pathology, University of Heidelberg, Germany.
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BM
Helmke
Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
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S
Kehr
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Germany.
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A
Unterberg
Institute of Pharmacy, Freie Universität Berlin, Germany; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Germany.
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I
Ott
Institute of Pharmacy, Freie Universität Berlin, Germany; Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Austria.
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Gust
UMR 6509 Institut de Chimie, CNRS Université de Rennes, France.
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Deborde
UMR7509 CNRS and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), France; Center of Biochemistry, University of Heidelberg, Germany.
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Davioud-Charvet
UMR 6509 Institut de Chimie, CNRS Université de Rennes, France.
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Réau
Biochemistry and Molecular Biology, Justus Liebig University Giessen, Germany.
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K
Becker
Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Germany.
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Herold-Mende
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D006801:Humans; D008297:Male; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D006046:Gold; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione
Cancer; Glioblastoma; Glutathione reductase; Gold(I)–phosphole complex; Redox system; Thioredoxin reductase