PUBLICATION
Baohuoside i suppresses breast cancer metastasis by downregulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 pathway
- Authors
- Wang, S., Wang, N., Huang, X., Yang, B., Zheng, Y., Zhang, J., Wang, X., Lin, Y., Wang, Z.
- ID
- ZDB-PUB-201002-16
- Date
- 2020
- Source
- Phytomedicine : international journal of phytotherapy and phytopharmacology 78: 153331 (Journal)
- Registered Authors
- Keywords
- Baohuoside i, Breast cancer metastasis, Cxcl1, Tumor-associated macrophages, Xiaopi formula
- MeSH Terms
-
- Animals
- Breast Neoplasms/drug therapy*
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology*
- Cell Line, Tumor
- Chemokine CXCL1/antagonists & inhibitors
- Chemokine CXCL1/genetics
- Chemokine CXCL1/metabolism*
- Coculture Techniques
- Down-Regulation/drug effects
- Drug Screening Assays, Antitumor
- Drugs, Chinese Herbal/chemistry
- Drugs, Chinese Herbal/pharmacology
- Embryo, Nonmammalian
- Female
- Flavonoids/pharmacology*
- Humans
- Macrophages/drug effects*
- Macrophages/metabolism
- Macrophages/pathology
- Mice, Inbred BALB C
- Neoplasm Metastasis
- Neoplastic Stem Cells/drug effects
- Xenograft Model Antitumor Assays
- Zebrafish/embryology
- PubMed
- 32911383 Full text @ Phytomedicine
Citation
Wang, S., Wang, N., Huang, X., Yang, B., Zheng, Y., Zhang, J., Wang, X., Lin, Y., Wang, Z. (2020) Baohuoside i suppresses breast cancer metastasis by downregulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology. 78:153331.
Abstract
Background Breast cancer is the most common malignancy in women and metastasis is the leading cause of breast cancer-related deaths. Our previous studies have shown that XIAOPI formula, a newly approved drug by the State Food and Drug Administration of China (SFDA), can dramatically inhibit breast cancer metastasis by modulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 (TAMs/CXCL1) pathway. However, the bioactive compound accounting for the anti-metastatic effect of XIAOPI formula remains unclear.
Purpose This study was designed to separate the anti-metastatic bioactive compound from XIAOPI formula and to elucidate its action mechanisms.
Study design/methods TAMs/CXCL1 promoter activity-guided fractionation and multiple chemical structure identification approaches were conducted to screen the bioactive compound from XIAOPI formula. Breast cancer cells and TAMs were co-cultured in vitro or co-injected in vivo to simulate their coexistence. Multiple molecular biology experiments, zebrafish breast cancer xenotransplantation model and mouse breast cancer xenografts were applied to validate the anti-metastatic activity of the screened compound.
Results Bioactivity-guided fractionation identified baohuoside I (BHS) as the key bioactive compound of XIAOPI formula in inhibiting TAMs/CXCL1 promoter activity. Functional studies revealed that BHS could significantly inhibit the migration and invasion as well as the expression of metastasis-related proteins in both human and mouse breast cancer cells, along with decreasing the proportion of breast cancer stem cells (CSCs). Furthermore, BHS could suppress the M2 phenotype polarization of TAMs and therefore attenuate their CXCL1 expression and secretion. Notably, mechanistic investigations validated TAMs/CXCL1 as the crucial target of BHS in suppressing breast cancer metastasis as exogenous addition of CXCL1 significantly abrogated the anti-metastatic effect of BHS on breast cancer cells. Moreover, BHS was highly safe in vivo as it exhibited no observable embryotoxicity or teratogenic effect on zebrafish embryos. More importantly, BHS remarkably suppressed breast cancer metastasis and TAMs/CXCL1 activity in both zebrafish breast cancer xenotransplantation model and mouse breast cancer xenografts.
Conclusion This study not only provides novel insights into TAMs/CXCL1 as a reliable screening target for anti-metastatic drug discovery, but also suggests BHS as a promising candidate drug for metastatic breast cancer treatment.
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping