Potentiation of Sorafenib’s Action by Berberine via Suppression of the mTOR Signaling Pathway in Human Hepatoma Cells

Sorafenib (SOR) is the first-line treatment for advanced hepatocellular carcinoma (HCC), while its therapeutic efficacy is unsatisfactory. Clinical studies suggest that combination therapy holds significant therapeutic potential to enhance SOR's efficacy. Berberine (BBR), a multiple-targeted agent, shows great promise in combination therapy. This study aims to investigate whether BBR can enhance SOR's effect in vitro and in vivo, and to elucidate the underlying mechanisms. We selected BEL-7402 cells and Huh7 cells for our investigation and explored the effect of BBR on the sensitivity of SOR using the cell counting kit-8 assay, cell cycle analysis, reactive oxygen species (ROS) detection assay, Annexin V/PI staining, western blotting, and the construction of tumor xenograft models. Our findings demonstrate that BBR not only enhances the proliferation-inhibitory effects, apoptosis, and ROS generation induced by SOR, but also sensitizes tumor xenograft models to SOR. Notably, this synergistic effect is found to depend on AMPK activation and the inhibition of the mTOR signaling pathway, a mechanism coincident with that of metformin (MET). Furthermore, our results reveal that BBR exhibits a stronger synergistic effect with SOR compared to MET. These results may contribute to developing innovative combination strategies for the treatment of advanced HCC.