RT Journal Article
T1 Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage
A1 Camano, Sonia
A1 Lázaro Fernández, Alberto
A1 Moreno Gordaliza, María Estefanía
A1 Torres, A. M.
A1 Lucas, Carmen de
A1 Humanes, Blanca
A1 Lázaro, José A.
A1 Gómez Gómez, María Milagros
A1 Bosca Gomar, Lisardo
A1 Tejedor Jorge, Alberto
AB 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.
PB American Society for Pharmacology and Experimental Therapeutics
SN 0022-3565
YR 2010
FD 2010
LK https://hdl.handle.net/20.500.14352/42738
UL https://hdl.handle.net/20.500.14352/42738
LA spa
NO Camano, S., Lázaro Fernández, A., Moreno Gordaliza, E. et al. «Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage». Journal of Pharmacology and Experimental Therapeutics, vol. 334, n.o 2, agosto de 2010, pp. 419-29. DOI.org (Crossref), https://doi.org/10.1124/jpet.110.165779.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Fondo de Investigaciones Sanitarias
NO Comunidad de Madrid
NO Fundación Mutua Madrileña
DS Docta Complutense
RD 9 abr 2025