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

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Humanes, Blanca and Lázaro, Alberto and Camano, Sonia and Moreno Gordaliza, Estefanía and Lázaro, José A. and Blanco Codesido, Montserrat and Lara, José M. and Ortiz, Alberto and Gómez Gómez, M.Milagros and Martín Vasallo, Pablo and Tejedor, Alberto (2012) Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats. Kidney International, 82 (6). pp. 652-663. ISSN 1523-1755 (On line), 0085-2538 (Print)

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Official URL: http://www.kidney-international.org/article/S0085-2538(15)55616-0/fulltext



Abstract

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.


Item Type:Article
Uncontrolled Keywords:apoptosis; cilastatin; cisplatin; nephroprotection; nephrotoxicity
Subjects:Sciences > Chemistry > Analytic chemistry
ID Code:44669
Deposited On:15 Sep 2017 11:22
Last Modified:18 Sep 2017 10:12

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