Exploring the mechanism by which quercetin re-sensitizes breast cancer to paclitaxel: network pharmacology, molecular docking, and experimental verification

This study is aimed to explore the potential molecular mechanism of quercetin reversing paclitaxel (PTX) resistance in breast Cancer (BC) by network pharmacology, molecular docking, and experimental verification. Pharmacological platform databases are used to predict quercetin targets and BC PTX-resistance genes and constructed the expression profile of quercetin chemosensitization. The overlapping targets were input into the STRING database and used Cytoscape v3.9.0 to construct the protein-protein interaction (PPI) network. Subsequently, these targets were performed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses and molecular docking. Finally, we further detected the potential role of quercetin in improving PTX sensitivity in BC in vitro experiments. Compounds and targets screening hinted that 220 quercetin predicted targets, 244 BC PTX resistance-related genes, and 66 potential sensitive target genes (PSTGs). Network pharmacology screening revealed the top-15 crucial targets in PPI network of quercetin reversing the sensitivity of BC to PTX. KEGG analysis revealed that they were mainly enriched in the EGFR/ERK signaling pathway. Molecular docking showed that both quercetin and PTX could stably bind to the key targets in the EGFR/ERK signaling pathway. In vitro experiments further confirmed that quercetin inhibited the key targets in the EGFR/ERK axis to the suppression of cell proliferation and promotion of Apoptosis in PTX-resistance BC cells, and restoring the activity of the resistant cells to PTX. Our results suggested that quercetin increased the sensitivity of BC to PTX through inhibiting EGFR/ERK axis, and it is an effective treatment for reversing PTX resistance.

Breast cancer; EGFR/ERK axis; Network pharmacology; Paclitaxel resistance; Quercetin.