National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China; Key Laboratory for Evaluation on Anti-tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang 330006, China.
National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China; Key Laboratory for Evaluation on Anti-tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang 330006, China.
Toxicol Appl Pharmacol. 2021 Dec 1;432:115755. doi: 10.1016/j.taap.2021.115755. Epub 2021 Oct 18.
The polarization of macrophages has been previously demonstrated to be closely related to immune and inflammatory processes in the tumorigenesis and progression of breast cancer. In the present study, Anemoside A3 (A3), an active compound from Pulsatilla saponins, was screened out and polarized M0 macrophages into the classically activated macrophages (M1-phenotype). We found that A3 is an activator of TLR4/NF-κB/MAPK signaling pathway. A3 increased the expression of CD86+ (a marker of M1 macrophage) in M0 macrophage, and increased the typical M1 macrophage pro-inflammatory cytokines TNF-α, and IL-12 expression in a TLR4-dependent manner. A macrophage-cancer cell co-culture system was established to evaluate whether A3 can could switch tumor-associated macrophages (TAMs) to the M1-phenotype. In the co-culture system, A3 increased the expression of IL-12 in macrophages, whereby suppressing MCF-7 breast cancer cell line proliferation and VEGF-mediated angiogenesis. Moreover, A3 induced M1 macrophage polarization in the 4 T1 murine breast cancer model and effectively inhibited tumor growth and tumor angiogenesis. Collectively, these findings indicated that A3 induced M1 macrophages polarization to repress breast tumorigenesis via targeting the TLR4/NF-κB/MAPK signaling pathway. This study provides a rationale for utilizing traditional Chinese medicine extracts in the immunotherapy of breast cancer.
巨噬细胞的极化已被证明与乳腺癌的发生和发展中的免疫和炎症过程密切相关。在本研究中，从白头翁皂苷中筛选出活性化合物苍术苷 A3（A3），并将 M0 巨噬细胞极化为经典激活的巨噬细胞（M1 表型）。我们发现 A3 是 TLR4/NF-κB/MAPK 信号通路的激活剂。A3 增加了 M0 巨噬细胞中 CD86+（M1 巨噬细胞的标志物）的表达，并以 TLR4 依赖性方式增加了典型的 M1 巨噬细胞促炎细胞因子 TNF-α和 IL-12 的表达。建立了巨噬细胞-癌细胞共培养系统，以评估 A3 是否可以将肿瘤相关巨噬细胞（TAMs）转化为 M1 表型。在共培养系统中，A3 增加了巨噬细胞中 IL-12 的表达，从而抑制 MCF-7 乳腺癌细胞系的增殖和 VEGF 介导的血管生成。此外，A3 在 4T1 小鼠乳腺癌模型中诱导 M1 巨噬细胞极化，并有效抑制肿瘤生长和肿瘤血管生成。总之，这些发现表明，A3 通过靶向 TLR4/NF-κB/MAPK 信号通路诱导 M1 巨噬细胞极化，从而抑制乳腺癌的发生。这项研究为利用中药提取物进行乳腺癌的免疫治疗提供了依据。
