Modulation of FOXO3 Transcriptional Regulation by Cisplatin and Curcumin in Human Embryonic Kidney Cells

Cisplatin is a highly effective anti-neoplastic agent, but its clinical application is limited by its association with severe nephrotoxicity. Although extensive research has identified several mechanisms underlying cisplatin-induced nephrotoxicity, the precise molecular pathways remain incompletely understood. Recent studies have highlighted the role of intrinsic survival, senescence, and longevity signaling pathways, including those governed by the FOXO3 transcription factor. In this study, we examined the effects of cisplatin and curcumin on the DNA methylation status and mRNA expression of FOXO3 in human embryonic kidney (HEK293) cells. Our results indicate that the FOXO3 promoter is methylated in cisplatin-treated cells, and that cisplatin regulates FOXO3 transcription in a dose-dependent manner. Quantitative RT-qPCR revealed that moderate cytotoxic concentrations of cisplatin (10 and 40 µM) significantly downregulate FOXO3 mRNA. Furthermore, co-treatment with the antioxidant curcumin successfully restored and enhanced FOXO3 expression at moderate cisplatin doses (10 µM) but failed to rescue expression at high doses (40 µM). Moreover, curcumin treatment (10 µM) reverses the effects of low-dose, but not high-dose, cisplatin (40 and 60 µM). Taken together, these findings provide a foundation for understanding the epigenetic and transcriptional regulation of FOXO3 and highlight its potential as a target for antioxidant-mediated nephroprotection and its role in cell survival.