Dietary antioxidant quercetin overcomes the acquired resistance of Sorafenib in Sorafenib-resistant hepatocellular carcinoma cells through epidermal growth factor receptor signaling inactivation

Sorafenib (SOR) is a molecular targeting agent commonly utilized as a primary treatment for advanced and inoperable hepatocellular carcinoma (HCC). Regrettably, the effectiveness of SOR is frequently hindered by the resistance of multiple HCC cases. The current investigation endeavors to examine the potential of the natural product quercetin (QUE) in reversing the acquired resistance of SOR-resistant cells, known as Huh7(R), to SOR. Moreover, this study aims to elucidate the underlying molecular mechanism that contributes to this phenomenon. The results demonstrated that QUE significantly impeded proliferation and stimulated apoptosis in Huh7(R) cells, while also suppressing the growth of transplanted tumors. The impact of QUE enhanced the efficacy of SOR treatment for Huh7(R). Additionally, bioinformatic and western blot analyses indicated that the underlying mechanisms may be associated with EGFR tyrosine kinase inhibitor resistance, the PI3K-AKT signaling pathway, and HCC. Furthermore, molecular docking and dynamics simulation assays revealed that QUE exhibited strong affinity and stability towards its hub targets, EGFR and AKT1. It is noteworthy that the activation of EGFR by its ligand, EGF, mitigated the effects of co-treatment with QUE and SOR. These findings suggest that QUE might potentially serve as a therapeutic agent in treating as well as facilitating SOR against Huh7(R) cells, which has substantial clinical and research implications for the treatment of acquired resistance to SOR in HCC.