Cisplatin-Induced Apoptosis Is Enhanced by Hypoxia and by Inhibition of Mitochondria in Renal Collecting Duct Cells

Cisplatin is a widely used chemotherapeutic agent. Here we show that cisplatin induces apoptosis in renal collecting duct-derived cells (MDCK-C7 cells, resembling principal cells) in a dose-dependent manner. Additionally, we studied the role of mitochondria in this process by inhibition of the mitoc...

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Bibliographic Details
Published in:Toxicological sciences 2005-05, Vol.85 (1), p.735-742
Main Authors: Schwerdt, Gerald, Freudinger, Ruth, Schuster, Claudia, Weber, Florian, Thews, Oliver, Gekle, Michael
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - toxicity
apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Caspase 3
Caspases - metabolism
Cell Hypoxia
Cell Line
Cell Survival - drug effects
cisplatin
Cisplatin - toxicity
collecting duct
Dogs
Hydrogen-Ion Concentration
hypoxia
Kidney Tubules, Collecting - cytology
Kidney Tubules, Collecting - drug effects
Kidney Tubules, Collecting - metabolism
mitochondria
Mitochondria - drug effects
Mitochondria - enzymology
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Summary:Cisplatin is a widely used chemotherapeutic agent. Here we show that cisplatin induces apoptosis in renal collecting duct-derived cells (MDCK-C7 cells, resembling principal cells) in a dose-dependent manner. Additionally, we studied the role of mitochondria in this process by inhibition of the mitochondrial respiratory chain, the F1Fo-ATP synthase or by uncoupling. The role of intra- and extracellular pH in apoptosis induction was investigated. Activation of caspase-3 and DNA ladder formation were used to monitor the apoptotic response. When cells were incubated with inhibitors of the mitochondrial respiratory chain or an inhibitor of the ATP-synthase, cisplatin-induced apoptosis was markedly enhanced. Mitochondrial blockade led to enhanced production of lactic acid. Also, anoxia potentiated the cisplatin-induced caspase-3 activation. Neither intra- nor extracellular pH had an influence on caspase-3 activation at low cisplatin concentrations. Acidic conditions (pH 6.8) potentiated the caspase-3 activation when high (100 μM) cisplatin concentrations were used. We demonstrate that intact mitochondria are important to prevent cisplatin-induced apoptosis in MDCK-C7 cells and that acidic conditions can aggravate the toxic effects of cisplatin.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfi117