Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.
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.
Renal Physiopathology Laboratory, Department of Nephrology, IiSGM-Hospital General Universitario Gregorio Marañón, Universidad Complutense de Madrid, Madrid, Spain.
Blanca
B
Humanes
Alberto
A
Lazaro
Sonia
S
Camano
Estefanía
E
Moreno-Gordaliza
Jose A
JA
Lazaro
Montserrat
M
Blanco-Codesido
Jose M
JM
Lara
Alberto
A
Ortiz
Maria M
MM
Gomez-Gomez
Pablo
P
Martín-Vasallo
Alberto
A
Tejedor
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D015377:Cilastatin / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013552:Swine
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D058851:GPI-Linked Proteins; D011480:Protease Inhibitors; D015377:Cilastatin; D003404:Creatinine; D004150:Dipeptidases; C549872:dipeptidase 1; D002945:Cisplatin