Glycosylated Delphinidins, Natural Antioxidants, Functionally Modulate the COX-2/PGE₂ Axis and Downregulate MDR1 in...

The multidrug resistance (MDR) phenotype, mediated by transporters such as MDR1/P-glycoprotein (P-gp), represents a critical obstacle in the treatment of glioblastoma (GB). Natural antioxidants such as glycosylated delphinidins-anthocyanins abundant in Chilean berries, particularly the native species Aristotelia chilensis (maqui)-have emerged as bioactive compounds that modulate inflammation and cancer-related pathways. In this context, the regulation of inflammation-associated signaling pathways, including COX-2 and NF-κB, represents a potential strategy to overcome chemoresistance. In this study, we evaluated the effect of delphinidin-3-glucoside (DEL-3) on the COX-2/PGE₂ axis, MDR1 expression, and sensitivity to chemotherapeutic agents in U87-MG and GBM38 glioblastoma cells and in an NOD-SCID xenograft model using ELISA, RT-qPCR, Western blot, and luciferase reporter assays. DEL-3 reduced PGE₂ production, consistent with functional modulation of the COX-2/PGE₂ pathway, and downregulated MDR1 expression at both transcriptional and protein levels, in agreement with reduced promoter activity. Functionally, combined treatment with DEL-3 and MDR1-substrate chemotherapeutic agents enhanced cytotoxicity in U87-MG cells. Although DEL-3 did not significantly reduce tumor growth in a NOD-SCID xenograft model, MDR1 expression was reduced in treated tumors, indicating in vivo modulation of the target. Overall, these findings suggest that DEL-3, as a natural antioxidant, modulates inflammation-associated mechanisms and downregulates MDR1, thereby potentially enhancing the sensitivity of glioblastoma cells to MDR1-substrate chemotherapeutic agents.