Cilastatin attenuates cisplatin-induced proximal tubular cell damage.
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.
Camano
Sonia
S
Renal Physiopathology Laboratory, Department of Nephrology, Hospital General Universitario Gregorio Maranon, 28007 Madrid, Spain.
Lazaro
Alberto
A
Moreno-Gordaliza
Estefania
E
Torres
Ana M
AM
de Lucas
Carmen
C
Humanes
Blanca
B
Lazaro
Jose A
JA
Milagros Gomez-Gomez
M
M
Bosca
Lisardo
L
Tejedor
Alberto
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015377:Cilastatin / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D015377:Cilastatin; D004247:DNA; D004150:Dipeptidases; C038937:dipeptidase; D002945:Cisplatin