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

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.