Quercetin overcomes gemcitabine resistance in pancreatic cancer by targeting TOP2A and WNT-β-catenin signaling

BACKGROUND Pancreatic cancer remains one of the most lethal malignancies with limited therapeutic options and frequent development of chemoresistance.Radix Bupleuri, a traditional Chinese medicine, hasshown anticancer properties, but its active components and molecular mechanisms in pancreatic cancer treatment remain unclear.AIM To suggest that quercetin may overcome gemcitabine resistance in pancreatic cancer, potentially through TOP2A targeting and associated suppression of WNT-β-catenin signaling, warranting further investigation as a candidate therapeutic approach for the management of chemoresistant pancreatic cancer.METHODS Bioinformatics analysis identified potential therapeutic targets from Radix Bupleuri compounds and pancreatic cancer-related genes.Gemcitabine-resistant pancreatic cancer cell lines were established and treated with Radix Bupleuri extract and quercetin.DNA TOP2A expression was modulated through knockdown and overexpression approaches.Cell viability, apoptosis, migration, and invasion were 5 / 66 assessed.WNT-β-catenin signaling pathway components were analyzed.Xenograft mouse models were used to evaluate in vivo therapeutic efficacy.RESULTS Quercetin was identified as a key compound targeting TOP2A, which was significantly overexpressed in pancreatic cancer tissues and associated with poor prognosis.Gemcitabine-resistant cells showed elevated TOP2A expression and enhanced sensitivity to quercetin treatment.Quercetin reduced TOP2A protein stability through ubiquitin-mediated degradation and inhibited WNT-β-catenin signaling.TOP2A knockdown enhanced gemcitabine sensitivity and suppressed malignant behaviors, while TOP2A overexpression rescued quercetin-induced effects.In xenograft models, quercetin significantly enhanced gemcitabine efficacy by reducing tumor growth and promoting apoptosis.CONCLUSION Quercetin from Radix Bupleuri overcomes gemcitabine resistance in pancreatic cancer potentially through TOP2A targeting and associated suppression of WNT-β-catenin signaling.This suggests that quercetin may represent a candidate therapeutic strategy worthy of further investigation in the context of chemoresistant pancreatic cancer.