Comparison of the nephroprotective effects of non-steroidal anti-inflammatory drugs on cisplatin-induced nephrotoxicity in vitro and in vivo
Comparison of the nephroprotective effects of non-steroidal anti-inflammatory drugs on cisplatin-induced nephrotoxicity in vitro and in vivo
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非甾体类抗炎药对顺铂所致肾毒性肾保护作用的体内外比较
DOI：
10.1016/j.ejphar.2020.173339
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发表时间：
2020-10-05
影响因子：
5
通讯作者：
Kobayashi, Masaki
中科院分区：
文献类型：
--
作者：
Okamoto, Keisuke;Saito, Yoshitaka;Kobayashi, Masaki
顺铂（CDDP）是一种抗癌药物，通常用于治疗几种类型的癌症。CDDP诱导的肾毒性（CIN）是与使用CDDP相关的最严重的不良事件之一。有人认为，非甾体类抗炎药（NSAID）的联合给药是CIN的一个风险因素。然而，影响CIN的具体NSAID和这种相互作用的确切机制仍不清楚。因此，我们的目的是评估NSAID对CDDP诱导的体外细胞毒性的影响，并在体内证实结果。使用正常大鼠肾细胞（NRK-52 E细胞）的上皮样克隆，我们评估了17种NSAID对CDDP诱导的细胞毒性的影响，同时使用MTT法。此外，我们评估了两种非甾体抗炎药，显着减弱或增强CDDP诱导的细胞毒性，在体内。Wistar大鼠用CDDP（5 mg/kg，i. p.，第1天）和NSAID（p.o.，第1-4天），并在第5天切除肾脏。我们的研究结果表明，一些非甾体类抗炎药衰减，而其他增强CDDP诱导的细胞毒性。塞来昔布显着减弱和氟比洛芬显着增强细胞功能障碍的CDDP。这些结果在体内重现，与CDDP组相比，塞来昔布降低了肾损伤分子1（Kim-1）mRNA的表达，氟比洛芬增加了肾损伤分子1（Kim-1）mRNA的表达。此外，塞来昔布增加了体外qPCR定量的抗氧化剂和自噬标志物，并防止了体内CDDP诱导的体重下降。总之，我们发现塞来昔布在体外和体内均能显著减弱CIN。
Cisplatin (CDDP) is an anticancer drug, often used in the treatment of several types of cancers. CDDP-induced nephrotoxicity (CIN) is one of the most severe adverse events associated with the use of CDDP. It has been suggested that the co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) is a risk factor for CIN. However, the specific NSAIDs that affect CIN and the precise mechanisms underlying this interaction remain unclear. Hence, we aimed to evaluate the effect of NSAIDs on CDDP-induced cytotoxicity in vitro and confirmed the results in vivo. Using the epithelioid clone of the normal rat kidney cells (NRK-52E cells), we assessed the effects of 17 NSAIDs on CDDP-induced cytotoxicity all at once using the MTT assay. Furthermore, we evaluated two NSAIDs, which significantly attenuated or enhanced CDDP-induced cytotoxicity, in vivo. Wistar rats were treated with CDDP (5 mg/kg, i.p., day 1) and NSAIDs (p.o., day 1-4), and the kidneys were excised on day 5. Our results demonstrated that several NSAIDs attenuated, while others enhanced CDDP-induced cytotoxicity. Celecoxib significantly attenuated and flurbiprofen markedly enhanced cell dysfunction by CDDP. These results were reproduced in vivo as celecoxib decreased and flurbiprofen increased the expression of kidney injury molecule 1 (Kim-1) mRNA, a sensitive kidney injury marker, compared to the CDDP group. Moreover, celecoxib increased the antioxidant and autophagy markers quantified by qPCR in vitro and prevented a decrease in body weight induced by CDDP in vivo. In conclusion, we revealed that celecoxib significantly attenuated CIN in vitro and in vivo.