Anemoside A3 activates TLR4-dependent M1-phenotype macrophage polarization to represses breast tumor growth and angiogenesis

Toxicol Appl Pharmacol. 2021 Dec 1;432:115755. doi: 10.1016/j.taap.2021.115755. Epub 2021 Oct 18.

Abstract

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.

Keywords: Anemoside A3; Angiogenesis; Breast cancer; Macrophage polarization; Toll-like receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Coculture Techniques
  • Cytokines / metabolism
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic*
  • Phenotype
  • Saponins / pharmacology*
  • Signal Transduction
  • THP-1 Cells
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / metabolism
  • Triterpenes / pharmacology*
  • Tumor Burden / drug effects
  • Tumor-Associated Macrophages / drug effects*
  • Tumor-Associated Macrophages / metabolism

Substances

  • Angiogenesis Inhibitors
  • Cytokines
  • NF-kappa B
  • Saponins
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Triterpenes
  • anemoside A3
  • Mitogen-Activated Protein Kinases