Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats
Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats
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DOI：
10.1038/ki.2012.199
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发表时间：
2012-09-01
影响因子：
19.6
通讯作者：
Tejedor, Alberto
中科院分区：
文献类型：
--
作者：
Humanes, Blanca;Lazaro, Alberto;Tejedor, Alberto
顺铂是一种因肾毒性而受损的抗癌药物;然而，限制这种不良反应可能允许使用更高的剂量来改善其疗效。西司他丁是一种肾脱氢肽酶I的小分子抑制剂，可防止体外近端肾小管细胞发生顺铂诱导的凋亡。在这里，我们探讨了这些发现的体内相关性和顺铂治疗大鼠肾细胞保护的特异性。顺铂增加血清尿素氮和肌酐水平，以及钠排泄分数。顺铂降低肾小球滤过率，促进组织学肾损伤和肾皮质中许多促凋亡蛋白的表达，增加Bax/Bcl 2比值，以及肾组织和尿液中的氧化应激。西司他丁降低了所有这些特征，保留了肾功能，但没有改变顺铂的药代动力学曲线下面积。西司他丁不能阻止顺铂诱导的宫颈癌、结肠癌、乳腺癌和膀胱癌细胞系的死亡。因此，西司他丁具有预防顺铂肾毒性而不损害其抗癌功效的潜力。
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.