Comparison of the nephroprotective effects of non-steroidal anti-inflammatory drugs on cisplatin-induced nephrotoxicity in vitro and in vivo

Abstract

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.