Pentagalloyl glucose reverses chemoresistance in triple-negative breast cancer via EMT inhibition and miRNA modulation

Triple-negative breast cancer (TNBC) presents a major clinical challenge due to its aggressive behavior, limited targeted therapies, and frequent development of chemoresistance. Resistance to doxorubicin (DOX), a key chemotherapeutic agent, is often associated with epithelial-mesenchymal transition (EMT), overexpression of multidrug resistance (MDR) proteins, and dysregulation of microRNAs (miRNAs). This study investigates the potential of pentagalloyl glucose (PGG), a naturally occurring polyphenol, to overcome DOX resistance in TNBC cells by targeting EMT, miRNA expression, and MDR transporter activity. DOX-resistant MDA-MB-231/ADR cells were established and characterized. The cytotoxic and chemosensitizing effects of PGG were evaluated through MTT assays, apoptosis analysis, migration and invasion assays, Western blotting, miRNA sequencing, qRT-PCR, and drug accumulation studies. PGG significantly restored DOX sensitivity in resistant TNBC cells, as demonstrated by a reduction in the half-maximal inhibitory concentration (IC₅₀) and increased apoptosis. An EMT reversal effect was observed through upregulation of E-cadherin and downregulation of ZEB1 and vimentin, accompanied by reduced cell migration and invasion. miRNA profiling revealed the upregulation of miR-200c-3p and other tumor-suppressive miRNAs. Notably, overexpression of miR-200c-3p alone enhanced chemosensitizing and DOX-induced apoptosis in MDA-MB-231/ADR cells, highlighting its role in drug sensitivity. Additionally, PGG reduced the expression of P-glycoprotein (P-gp) and multidrug resistance protein-1(MRP-1), increased intracellular DOX accumulation, and inhibited efflux activity. In conclusion, PGG reverses DOX resistance in TNBC cells through multiple mechanisms involving EMT inhibition, MDR suppression, and restoration of miR-200c-3p expression. These findings suggest that PGG holds promise as an adjuvant therapeutic agent for managing multidrug-resistant TNBC.