Synergistic effect of ursodeoxycholic acid on the antitumor activity of sorafenib in hepatocellular carcinoma cells via modulation of STAT3 and ERK

Sorafenib has been approved for the treatment of advanced stage hepatocellular carcinoma but has limited efficacy. Ursodeoxycholic acid exerts cytoprotective activities in hepatocytes and is believed to suppress tumorigenesis through cell cycle arrest and induction of apoptosis. The present study examined whether co-treatment with ursodeoxycholic acid has a synergistic effect on the antitumor activity of sorafenib in hepatocellular carcinoma cells. Notably, co-treatment with both agents more effectively inhibited cell proliferation than sorafenib or ursodeoxycholic acid alone. Furthermore, co-treatment inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and activated extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase, accompanied by excessive intracellular reactive oxygen species generation in hepatocellular carcinoma cells. Thus, chemotherapy with sorafenib and ursodeoxycholic combination may be efficacious in hepatocellular carcinoma by inhibiting cell proliferation and inducing apoptosis through reactive oxygen species-dependent activation of ERK and dephosphorylation of STAT3. The present findings may represent a promising therapeutic strategy for patients with advanced hepatocellular carcinoma.