Protective Effect of Palonosetron against Cisplatin-Induced Cytotoxicity via Decreased Phosphorylation of p38

The dose-limiting nephrotoxicity of cisplatin (CDDP) is attributed to its accumulation in renal epithelial cells, mediated by uptake via human organic cation transporter 2 (hOCT2) and efflux via human multidrug and toxin extrusion 1 (hMATE1), followed by apoptosis induction via p38 phosphorylation. Recently, we demonstrated that the incidence of CDDP-induced nephrotoxicity was significantly lower in patients receiving palonosetron, a 5-hydroxytryptamine 3 receptor antagonist (5-HT₃RA), than in those receiving other 5-HT₃RAs (ondansetron, ramosetron, and granisetron). However, the underlying mechanism through which palonosetron induces a renoprotective effect remains unclear. In this study, we investigated the effects of 5-HT₃RAs (palonosetron, ondansetron, ramosetron, and granisetron) on hOCT2- and hMATE1-mediated transport of CDDP, as well as on CDDP-induced cytotoxicity. In the CDDP uptake study, none of these 5-HT₃RAs inhibited hOCT2-mediated transport of CDDP at concentrations of 0.1 and 1 μM, except for 10 μM (above clinical concentration). However, ondansetron and ramosetron, unlike palonosetron or granisetron, potently inhibited the hMATE1-mediated transport of CDDP at concentrations of 0.1 and 1 μM. In human embryonic kidney (HEK293) and porcine kidney (LLC-PK₁) epithelial cells, all the tested 5-HT₃RAs (1 μM), except granisetron, reduced CDDP-induced cytotoxicity. Moreover, co-incubation with palonosetron, ondansetron, and ramosetron suppressed CDDP-induced p38 phosphorylation in HEK293 cells. Thus, these findings suggest that concomitant treatment with palonosetron reduces CDDP-induced cytotoxicity by inhibiting p38 phosphorylation, but does not inhibit the hOCT2-mediated transport of CDDP. The present findings provide novel insights into the reduction of CDDP-induced cytotoxicity through concomitant palonosetron treatment.