Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage



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Camano, Sonia and Lázaro, Alberto and Moreno Gordaliza, Estefanía and Torres, A.M. and Lucas, Carmen de and Humanes, Blanca and Lázaro, José A. and Gómez Gómez, M.Milagros and Bosca, Lisardo and Tejedor, Alberto (2010) Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage. Journal of pharmacology and experimental therapeutics, 334 (2). pp. 419-429. ISSN 0022-3565 (Print), 1521-0103 (On line)

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A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatininduced 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 M) in the presence or absence of cilastatin (200 g/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 , Fas ligand). In contrast, cilastatin did not show any effects on cisplatintreated 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.

Item Type:Article
Uncontrolled Keywords:RPTECs, renal proximal tubular epithelial cells; OCT, organic cation transporter; DHP-I, dehydrodipeptidase I; DAPI, 4,6- diamidino-2-phenylindole; PBS, phosphate-buffered saline; PI, propidium iodide; FITC, fluorescein isothiocyanate; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; �m, mitochondrial transmembrane potential; CCCP, carbonyl cyanide 3-chlorophenylhydrazone; ICP/MS, inductively coupled plasma/mass spectrometry; SEC, size exclusion; TNF, tumor necrosis factor; Fas-L, Fas ligand; PCR, polymerase chain reaction; RPLPO, ribosomal phosphoprotein large PO subunit; ANOVA, analysis of variance; CFUs, colony-forming units; Pt, platinum; Ir, iridium.
Subjects:Sciences > Chemistry > Analytic chemistry
ID Code:44662
Deposited On:15 Sep 2017 10:00
Last Modified:18 Sep 2017 10:27

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