Inactivation of AKT/ERK Signaling and Induction of Apoptosis Are Associated With Amentoflavone Sensitization of Hepatocellular Carcinoma to Lenvatinib

AKT/ERK signaling transduction and anti-apoptosis effects have both been recognized as important mediators of hepatocellular carcinoma (HCC) progression. Targeting AKT/ERK signaling and mediating apoptosis may be beneficial for alleviating HCC growth. Lenvatinib, a tyrosine kinase inhibitor, has been approved by the FDA to treat HCC since 2018 as a monotherapy with limited efficacy. Amentoflavone, a biflavonoid in natural plants, has been shown to have the potential to suppress HCC progression in previous studies. Whether the combination of lenvatinib and amentoflavone may show superior HCC suppression is unclear.We used MTT, flow cytometry and western blotting assays to identify the role of lenvatinib and amentoflavone in both Hep3B and Huh7 cells.We found that amentoflavone enhances the suppressive effect of AKT/ERK signaling induced by lenvatinib and, thus, sensitizes HCC to lenvatinib. The intrinsic/extrinsic apoptosis pathways induced by lenvatinib were also boosted by amentoflavone.Amentoflavone sensitization of HCC to lenvatinib is associated with AKT/ERK inactivation and apoptosis induction.