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.