Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis
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�...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024004924 |
| _version_ | 1797328648413380608 |
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| author | Junfei Li Chenghui Zhu Zengyu Zhang Xiaorong Zheng Chunlei Wang Hongyan Zhang |
| author_facet | Junfei Li Chenghui Zhu Zengyu Zhang Xiaorong Zheng Chunlei Wang Hongyan Zhang |
| author_sort | Junfei Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T06:54:42Z |
| format | Article |
| id | doaj.art-2e27bbeec72244308efb60b87c1d51dc |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-08T06:54:42Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-2e27bbeec72244308efb60b87c1d51dc2024-02-03T06:37:34ZengElsevierHeliyon2405-84402024-01-01102e24461Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axisJunfei Li0Chenghui Zhu1Zengyu Zhang2Xiaorong Zheng3Chunlei Wang4Hongyan Zhang5Zhejiang Cancer Hospital, Hangzhou Institute of Medicine and Cancer (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, ChinaWannan Medical College, Wuhu, Anhui, 241000, ChinaThe Second School of Clinical Medicine, Zhejiang Chinese Medical University No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, ChinaZhejiang Cancer Hospital, Hangzhou Institute of Medicine and Cancer (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, ChinaZhejiang Cancer Hospital, Hangzhou Institute of Medicine and Cancer (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, ChinaZhejiang Cancer Hospital, Hangzhou Institute of Medicine and Cancer (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2405844024004924SorafenibHepatocellular carcinomaNF-κBPD-L1Paeoniflorin |
| spellingShingle | Junfei Li Chenghui Zhu Zengyu Zhang Xiaorong Zheng Chunlei Wang Hongyan Zhang Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis Heliyon Sorafenib Hepatocellular carcinoma NF-κB PD-L1 Paeoniflorin |
| title | Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis |
| title_full | Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis |
| title_fullStr | Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis |
| title_full_unstemmed | Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis |
| title_short | Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis |
| title_sort | paeoniflorin increases the anti tumor efficacy of sorafenib in tumor bearing mice with liver cancer via suppressing the nf κb pd l1 axis |
| topic | Sorafenib Hepatocellular carcinoma NF-κB PD-L1 Paeoniflorin |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024004924 |
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