Discovery of pentagalloylglucose as a dual GSTP1/ P-gp inhibitor uncovered by integrated computational and experimental approaches.

Abstract

Taxol remains a cornerstone therapy for non-small cell lung cancer, however, the development of acquired resistance continues to pose a significant clinical hurdle. Glutathione S-transferase P1 (GSTP1) and P-glycoprotein (P-gp) have been identified as key mediators of this multi-drug resistance phenotype. Consequently, the dual-target inhibition of these proteins represents a promising therapeutic strategy to circumvent chemoresistance. Here, pentagalloylglucose has been identified as a potential dual GSTP1/P-gp inhibitor through virtual screening. Molecular dynamics simulations validated the stable binding conformations of pentagalloylglucose with both target proteins. Furthermore, microscale thermophoresis and cellular thermal shift assays confirmed the direct binding interaction between pentagalloylglucose and GSTP1, while enzymatic assays demonstrated its potent inhibitory efficacy against the enzyme. Notably, treatment with pentagalloylglucose significantly enhanced the intracellular accumulation of Rhodamine 123, thereby indicating effective inhibition of P-gp mediated efflux. This effect culminated in a marked restoration of taxol sensitivity in A549/Taxol resistant cells. Additionally, pentagalloylglucose treatment inhibited cell metastasis in a concentration-dependent manner, accompanied by the down-regulation of epithelial-mesenchymal transition-related genes. Transcriptomic analysis further revealed that pentagalloylglucose modulates multiple signaling pathways implicated in cell proliferation and metastasis. Collectively, these findings establish pentagalloylglucose as a promising dual-target inhibitor for overcoming taxol resistance. The strategy of simultaneously targeting GSTP1 and P-gp offers a viable approach for the treatment of drug-resistant lung adenocarcinoma, providing a robust scientific foundation for future drug development and structural optimization.