Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage
Cilastatin Attenuates Cisplatin-Induced Proximal Tubular Cell Damage
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DOI：
10.1124/jpet.110.165779
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发表时间：
2010-08-10
影响因子：
3.5
通讯作者：
Tejedor, Alberto
中科院分区：
文献类型：
--
作者：
Camano, Sonia;Lazaro, Alberto;Tejedor, Alberto
癌症治疗的一个主要领域是寻找针对顺铂诱导的肾毒性的保护策略。我们研究了西司他丁对顺铂诱导的肾近端小管细胞损伤的保护作用。西司他丁是肾脱氢二肽酶I（DHP-I）的特异性抑制剂，可阻止亚胺培南的水解及其在近曲小管中的蓄积。在存在或不存在西司他丁（200 μ g/ml）的情况下，用顺铂（1-30 μ M）处理近端细胞的原代培养物。通过不同的技术评估细胞凋亡和线粒体损伤。顺铂的摄取和DNA结合的电感耦合等离子体光谱法测定。HeLa细胞用于控制西司他丁对顺铂的杀肿瘤活性的影响。顺铂以剂量和时间依赖性方式增加近端肾小管细胞中的细胞死亡、凋亡样形态、半胱天冬酶激活和线粒体损伤。西司他丁伴随治疗可减少顺铂诱导的变化。西司他丁还减少了DNA结合的铂，但没有改变死亡受体（Fas）或配体（肿瘤坏死因子α，Fas配体）的顺铂依赖性上调。相反，西司他丁对顺铂处理的HeLa细胞没有任何影响。肾DHP-I在HeLa细胞中几乎不存在。西司他丁减弱顺铂诱导的近端肾小管细胞死亡，而不降低顺铂在肿瘤细胞中的细胞毒活性。我们的研究结果表明，西司他丁对肾二肽酶的亲和力使这种效应特异性近端肾小管细胞，并可能与细胞内药物蓄积减少。因此，西司他丁给药可能是预防顺铂诱导的急性肾损伤的一种新策略。
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 mu M) in the presence or absence of cilastatin (200 mu g/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.