Baohuoside i suppresses breast cancer metastasis by downregulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 pathway
Baohuoside i suppresses breast cancer metastasis by downregulating the tumor-associated macrophages/C-X-C motif chemokine ligand 1 pathway
复制标题
保霍苷 i 通过下调肿瘤相关巨噬细胞/C-X-C 基序趋化因子配体 1 通路抑制乳腺癌转移
DOI：
10.1016/j.phymed.2020.153331
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发表时间：
2020-11-01
期刊：
影响因子：
7.9
通讯作者：
Wang, Zhiyu
中科院分区：
文献类型：
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作者：
Wang, Shengqi;Wang, Neng;Wang, Zhiyu
背景：乳腺癌是女性最常见的恶性肿瘤，转移是乳腺癌相关死亡的主要原因。本课题组前期研究表明，消痞方是国家食品药品监督管理局（SFDA）批准的新药，通过调节肿瘤相关巨噬细胞/C-X-C基序趋化因子配体1（TAMs/CXCL 1）通路，可显著抑制乳腺癌转移。目的：从消痞方中分离出抗肿瘤转移的活性成分，并阐明其作用机制。研究设计/方法：采用TAMS/CXCL 1启动子活性导向分离和多种化学结构鉴定方法，从消痞方中筛选出抗肿瘤转移的活性成分。将乳腺癌细胞和TAMS在体外共培养或在体内共注射以模拟它们的共存。结果：生物活性导向分级分离法确定宝藿苷I（BHS）为消痞方中抑制TAMS/CXCL 1启动子活性的关键活性化合物。功能研究表明，BHS能显著抑制人和小鼠乳腺癌细胞的迁移和侵袭，并能沿着降低乳腺癌干细胞（CSCs）的比例，抑制转移相关蛋白的表达。此外，BHS可以抑制TAMS的M2表型极化，从而减弱其CXCL 1的表达和分泌。值得注意的是，机制研究验证了TAMS/CXCL 1作为BHS抑制乳腺癌转移的关键靶标，因为外源性添加CXCL 1显著消除了BHS对乳腺癌细胞的抗转移作用。此外，BHS在体内是高度安全的，因为它对斑马鱼胚胎没有明显的胚胎毒性或致畸作用。更重要的是，BHS显着抑制乳腺癌转移和TAMS/CXCL 1活性在斑马鱼乳腺癌异种移植模型和小鼠乳腺癌异种transplantation.Conclusion：这项研究不仅提供了新的见解TAMS/CXCL 1作为一个可靠的筛选靶点的抗转移药物发现，但也表明BHS作为一个有前途的候选药物治疗转移性乳腺癌。
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 antimetastatic drug discovery, but also suggests BHS as a promising candidate drug for metastatic breast cancer treatment.