Document Detail


Cilastatin attenuates cisplatin-induced proximal tubular cell damage.
MedLine Citation:
PMID:  20435919     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.
Authors:
Sonia Camano; Alberto Lazaro; Estefania Moreno-Gordaliza; Ana M Torres; Carmen de Lucas; Blanca Humanes; Jose A Lazaro; M Milagros Gomez-Gomez; Lisardo Bosca; Alberto Tejedor
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-04-30
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  334     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-19     Completed Date:  2010-08-17     Revised Date:  2012-07-04    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  419-29     Citation Subset:  IM    
Affiliation:
Renal Physiopathology Laboratory, Department of Nephrology, Hospital General Universitario Gregorio Maranon, 28007 Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD95 / biosynthesis,  genetics
Antineoplastic Agents / toxicity*
Cell Death / drug effects
Cell Survival / drug effects
Cells, Cultured
Cilastatin / metabolism,  pharmacology*
Cisplatin / toxicity*
DNA / metabolism
Dipeptidases / antagonists & inhibitors*
Fas Ligand Protein / biosynthesis,  genetics
HeLa Cells
Humans
Kidney Tubules, Proximal / cytology,  drug effects*,  enzymology
Membrane Potential, Mitochondrial / drug effects
RNA, Messenger / biosynthesis
Swine
Tumor Necrosis Factor-alpha / biosynthesis,  genetics
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/Antineoplastic Agents; 0/Fas Ligand Protein; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 15663-27-1/Cisplatin; 82009-34-5/Cilastatin; 9007-49-2/DNA; EC 3.4.13.-/Dipeptidases; EC 3.4.13.18/dipeptidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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