Antiglioma activity of 2,2':6',2"-terpyridineplatinum(II) complexes in a rat model--effects on cellular redox metabolism.
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 (I(23)2N) and 2-mercaptopyridine (4'-chloro-2,2':6',2"-terpyridine)platinum nitrate (I(25)2N) 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 I(23)2N is not mediated by the induction of programmed cell death but rather by hTrxR inhibition and DNA intercalation leading to cell cycle arrest.
Ahmadi
Rezvan
R
Molecular Biology Laboratory, Department of Neurosurgery, University of Heidelberg, Germany.
Urig
Sabine
S
Hartmann
Marius
M
Helmke
Burkhard M
BM
Koncarevic
Sasa
S
Allenberger
Bianca
B
Kienhoefer
Christine
C
Neher
Markus
M
Steiner
Hans-Herbert
HH
Unterberg
Andreas
A
Herold-Mende
Christel
C
Becker
Katja
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D049109:Cell Proliferation; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D008297:Male; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051140:Selenoproteins / Q000032:analysis / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C511378:2-mercaptopyridine (4'-chloro-2,2'-6',2''-terpyridine)platinum(II); C511377:4-mercaptopyridine (4'-chloro-2,2'-6',2''-terpyridine)platinum(II); D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D051140:Selenoproteins; D010088:Oxidoreductases