Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis.

ABSTRACT

Background: Sorafenib (Sor) represents a first-line therapy for hepatocellular carcinoma (HCC); however, its efficacy is constrained by secondary failure, which limits its clinical use. Recent studies have indicated that the suppression of Programmed cell death-Ligand 1 (PD-L1) may potentiate Sor's anti-liver cancer effects; furthermore, PD-L1 expression is known to be regulated by NF-κB. Previous research has demonstrated that paeoniflorin (PF) downregulates the NF-κB axis, nevertheless, current research has not yet determined whether PF can synergistically enhance the efficacy of Sor against HCC by modulating the NF-κB/PD-L1 pathway. Methods: The study employed a H22 hepatoma-bearing mouse model, which was treated with PF, Sor, and their combination over a period of 12 days. The impact of PF and Sor on tumor growth, proliferation, apoptosis, T-cell subsets, IL-2 and IFN-γ production, and NF-κB and PD-L1 expression was assessed. Moreover, Splenic lymphocyte from normal mice and tumor cells from model mice were co-cultured in vitro, and the tumor-specific cytotoxic T lymphocyte activity was analyzed. In the final phase of the study, Huh-7 cells were stimulated with PF in combination with an NF-κB activator or inhibitor, and the subsequent production of NF-κB and PD-L1 was investigated. Results: PF and Sor exhibit a synergistic anti-tumor effect, compared to the use of Sor alone, the combined use of PF and Sor significantly increased the number of CD4+ and CD8+ T cells in tumor tissue, markedly enhanced the cytotoxic activity of tumor-specific cytotoxic T lymphocytes, and reversed the depletion of interleukin-2 and the increase in PD-L1 expression following Sor intervention. This combination also further reduced the level of IFN-γ in peripheral blood and the expression of NF-κB and PD-L1 in tumor tissue. Additionally, in vitro experiments confirmed that PF reduces the expression of PD-L1 in Huh-7 liver cancer cells by inhibiting NF-κB. Conclusions: PF plays a synergistic role of Sor inhibiting HCC progression by regulating the NF-κB/PD-L1 pathway.