Antiglioma activity of 2,2′:6′,2-terpyridineplatinum(II) complexes in a rat model—Effects on cellular redox metabolism

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• 作者：Rezvan Ahmadi ; Sabine Urig ; Marius Hartmann ; Burkhard M. Helmke ; Sasa Koncarevic ; Bianca Allenberger ; Christine Kienhoefer ; Markus Neher ; Hans-Herbert Steiner ; Andreas Unterberg et al.
• 关键词：Apoptosis ; Glioblastoma therapy ; Redox regulation ; Terpyridineplatinum(II) complexes ; Thioredoxin reductase ; Free radical
• 刊名：Free Radical Biology and Medicine
• 出版年：2006
• 出版时间：1 March 2006
• 年：2006
• 卷：40
• 期：5
• 页码：763-778
• 全文大小：993 K

文摘

The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4′-chloro-2,2′:6′,2-terpyridine)platinum nitrate (I₂₃2N) and 2-mercaptopyridine (4′-chloro-2,2′:6′,2-terpyridine)platinum nitrate (I₂₅2N) on glioblastoma in a rat model. These compounds show no or little cross-resistance with cisplatin and are thus of great clinical interest. Triple intravenous application of 25–35 mg/kg of the compounds led to a significant decrease of tumor growth as determined by magnetic resonance imaging. Metabolic as well as redox parameters in the blood of the animals were not altered. However, TrxR activity was significantly decreased in the tumor tissue, and redox parameters—including glutathione concentrations, total antioxidant status, and the activities of different antioxidant enzymes—showed tissue-specific variations. As indicated by different apoptotic markers, the antitumor activity of I₂₃2N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest.