Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats

• Published in: Kidney international Vol. 82; no. 6; pp. 652 - 663
• Main Authors: Humanes, Blanca, Lazaro, Alberto, Camano, Sonia, Moreno-Gordaliza, Estefanía, Lazaro, Jose A., Blanco-Codesido, Montserrat, Lara, Jose M., Ortiz, Alberto, Gomez-Gomez, Maria M., Martín-Vasallo, Pablo, Tejedor, Alberto
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.09.2012; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Area Under Curve; Biological and medical sciences; Biomarkers - blood; Blood Urea Nitrogen; Body Weight - drug effects; Cell Line, Tumor; cilastatin; Cilastatin - pharmacology; cisplatin; Cisplatin - pharmacokinetics; Cisplatin - toxicity; Creatinine - blood; Cytoprotection; Dipeptidases - antagonists & inhibitors; Dipeptidases - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerular Filtration Rate - drug effects; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - metabolism; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney - physiopathology; Kidney Diseases - blood; Kidney Diseases - chemically induced; Kidney Diseases - enzymology; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Kidney Diseases - prevention & control; Male; Medical sciences; Natriuresis - drug effects; Nephrology. Urinary tract diseases; nephroprotection; nephrotoxicity; Oxidative Stress - drug effects; Protease Inhibitors - pharmacology; Rats; Rats, Wistar; Swine; apoptosis; nephrotoxicity; cisplatin; nephroprotection; cilastatin; Antineoplastic agent; Nephrology; Rat; Enzyme; Toxicity; Rodentia; Cilastatin; Enzyme inhibitor; Cisplatin; Urology; Peptidases; Alkylating agent; Vertebrata; Mammalia; Efficiency; Cell death; Animal; Nephroprotection; Hydrolases; Nephrotoxicity; Platinum II Complexes; Apoptosis
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2012.199

Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.