Effects of Sensitized Sorafenib with a Paeoniflorin and Geniposide Mixture on Liver Cancer via the NF-κB-HIF-2α-SerpinB3 Pathway.

ABSTRACT

Purpose: This study focused on determining the anticancer effect of paeoniflorin and geniposide mixture (PFGS) combined with sorafenib (Sor) in hepatocellular carcinoma (HCC) and, in particular, whether PFGS increases the antitumor effect of Sor by modulating the NF-κB/HIF-2α/SerpinB3 pathway. Methods: The H22 hepatoma tumor-bearing mouse model was treated with PFGS, Sor, and a combination of the two drugs for 12 days. The effects of PFGS combined with Sor on tumor growth and apoptosis and the expression of NF-κB, HIF-2α, and SerpinB3 in tumor tissue were assessed. In addition, Sor-resistant hepatoma cells were treated with PFGS, Sor, and the combination of the two drugs in vitro. The effects of PFGS combined with Sor on cell proliferation and invasion and the protein expression of NF-κB p65, HIF-2α, and SerpinB3 were investigated. Results: PFGS combined with Sor treatment synergistically inhibited tumor growth in HCC tumor-bearing mice. Immunostaining showed that PFGS combined with Sor treatment significantly decreased the expression of Ki-67 and obviously induced apoptosis in the tumor compared with a single treatment. Similarly, PFGS combined with Sor treatment significantly downregulated the expression of NF-κB, HIF-2α, and SerpinB3 in the tumor compared with a single treatment. Additionally, PFGS combined with Sor markedly inhibited cell proliferation and invasion and activation of the NF-κB/HIF-2α/SerpinB3 pathway in Sor-resistant hepatoma cells compared with a single treatment. Conclusion: Our study demonstrated that PFGS synergistically increased the antiliver cancer effects of Sor by lowering activation of the NF-κB/HIF-2α/SerpinB3 pathway. These findings provided a scientific foundation for clinical studies using PFGS and Sor to treat liver cancer.