Quercetin Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells

Molecular targeted therapies play a crucial role in the management of hepatocellular carcinoma (HCC). Lenvatinib is a standard targeted agent for advanced HCC, while quercetin has emerged as a promising natural compound with anti-HCC potential. This study investigates the combined effect of quercetin and lenvatinib on HCC.

The human HCC cell line Huh7 and a nude mouse subcutaneous xenograft model were utilized. We evaluated cell proliferation, clonogenicity, invasion, migration, and apoptosis through Cell Counting Kit-8 (CCK-8), clonogenic, Transwell, and flow cytometry assays, respectively. Network pharmacology analysis was performed identify common targets. The protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X-protein (Bax), E-cadherin, N-cadherin, and protein tyrosine kinase 2 (PTK2) were assessed by Western blotting. In vivo experiments were conducted to validate the anti-tumor efficacy of the combination treatment.

The combination of quercetin and lenvatinib significantly enhanced inhibition of Huh7 cell proliferation, colony formation, invasion, and migration (p < 0.01) and promoted apoptosis (p < 0.01) compared to individual treatments. Mechanistically, the combination treatment decreased the expression of Bcl-2 and N-cadherin while upregulating Bax and E-cadherin. PTK2 was identified as a key shared target, and the combination most effectively suppressed its protein expression. In vivo, the combination group demonstrated a higher tumor inhibition rate (p < 0.01) and a Combination Index (CDI) of 0.753.

Quercetin significantly enhances the anti-tumor efficacy of lenvatinib, likely through synergistic inhibition of PTK2 expression.