Diclofenac potentiates the antitumor effect of cisplatin in a xenograft mouse model transplanted with cisplatin-resistant cells without enhancing cisplatin-induced nephrotoxicity

Abstract

Cisplatin (CDDP) is a well-known anticancer agent, and CDDP–induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while celecoxib reduces CIN, diclofenac does not appear to enhance it. Furthermore, we reported that diclofenac additively enhances the cytotoxic effect of CDDP on CDDP-resistant A549 cells (A549/DDP cells) and their spheroids. In addition, celecoxib reduces the cytotoxic effect of CDDP on A549/DDP cells while demonstrating an anticancer effect; however, it enhanced the effect of CDDP cytotoxicity on spheroids. Therefore, we evaluated the effects of diclofenac or celecoxib on CIN and the antitumor effect of CDDP in a xenograft mouse model transplanted with A549/DDP cells. Although CDDP did not decrease tumor size and tumor weight, these parameters were significantly reduced following co-administration with diclofenac when compared with the control group. Conversely, celecoxib marginally suppressed the antitumor effect of CDDP. Moreover, CDDP increased the mRNA levels of kidney injury molecule 1 (Kim-1), a renal disorder marker, in the kidneys of xenograft mice; treatment with celecoxib and diclofenac did not impact Kim-1 mRNA levels increased by CDDP. In conclusion, diclofenac potentiated the antitumor effect of CDDP without enhancing CIN.