Naringenin Enhances the Inhibitory Effect of Regorafenib on HepG2 Hepatocellular Carcinoma Cell Viability with Modulation of E-Cadherin and MRP1 Gene Expression

Hepatocellular carcinoma (HCC) is a life-threatening malignancy. Although regorafenib is used for HCC treatment, its clinical utility is limited by significant adverse effects. This study evaluated whether combining regorafenib with naringenin could enhance its anticancer activity against HepG2 cells. This study included seven groups of HepG2 cancer cells: an untreated control group, a naringenin-treated group (100 μM), a regorafenib-treated group (1 μM), and four groups receiving naringenin (100 μM) combined with decreasing concentrations of regorafenib (1, 0.75, 0.5, and 0.25 μM). Cell viability and the expression of E-cadherin and MRP1 were assessed. All treatments significantly reduced cell viability compared with the control group, with greater inhibition observed in the combination-treated groups than in the monotherapy groups. Combination treatment also increased E-cadherin expression and decreased MRP1 expression. The combination of regorafenib (1 μM) and naringenin (100 μM) exhibited the greatest growth inhibition, the highest E-cadherin, and the lowest MRP1 expression levels. Notably, combining the IC50 of naringenin with one-quarter of the regorafenib IC50 significantly enhanced E-cadherin expression and reduced MRP1 expression compared with regorafenib alone. The present findings suggest that naringenin enhances the anticancer effects of regorafenib in HepG2 cells and modulates E-cadherin and MRP1 gene expression.