Chen Xin, Beutler John A, McCloud Thomas G, Loehfelm Amy, Yang Lu, Dong Hui-Fang, Chertov Oleg Y, Salcedo Rosalba, Oppenheim Joost J, Howard O M Zack
The Basic Research Program, Science Applications International Corporation-Frederick, Inc. Gaithersburg, Maryland 20879, USA.
Clin Cancer Res. 2003 Aug 1;9(8):3115-23.
Increasing evidence suggests that interaction between the chemoattractant CXCL12/stromal cell-derived factor-1alpha and its receptor CXCR4 plays a pivotal role in the metastasis of various tumors. Our previous studies showed that multi-component Chinese herbal medicines inhibited the effects of CXCL12/CXCR4. As a result of sequential chromatographic fractionation of one herbal medicine ingredient, Lianqiao (fruit of Forsythia suspensa), we observed that tannins were, at least in part, responsible for this activity. The aim of this study was to assess the anti-CXCL12/CXCR4 activity of a commercial tannic acid and evaluate its potential to inhibit tumor cell migration and angiogenesis in vitro.
The inhibitory effect of tannic acid on CXCL12/CXCR4 was measured by chemotaxis assay, ligand binding assay, and fluorescence-activated cell sorter analysis. The antiangiogenic effect of tannic acid was assessed by in vitro endothelial cell tube formation.
Tannic acid, at nontoxic concentrations, specifically inhibited CXCL12-induced human monocyte migration (IC(50), 7.5 micro g/ml) but did not inhibit CCL2-, CCL3-, CCL5-, formylmethionylleucylphenylalanine (fMLP)-, or C5a-induced migration. The compound markedly blocked CXCL12 binding to THP-1 cells (IC(50), 0.36 micro g/ml). Tannic acid also inhibited CXCL12-induced, but not epidermal growth factor-induced, migration of MDA 231 breast tumor cells. Additionally, 0.5 micro g/ml of tannic acid selectively inhibited CXCL12-mediated, but not basic fibroblast growth factor- or endothelial cell growth supplement-mediated, bovine aorta endothelial cell capillary tube formation.
These studies indicate that tannic acid is a novel selective CXCL12/CXCR4 antagonist and consequently may provide a mechanistic basis for the reported antitumor and anti-inflammatory properties of tannic acid.
越来越多的证据表明，趋化因子CXCL12/基质细胞衍生因子-1α与其受体CXCR4之间的相互作用在多种肿瘤的转移中起关键作用。我们之前的研究表明，多成分中药可抑制CXCL12/CXCR4的作用。通过对一种中药成分连翘（连翘的果实）进行连续色谱分离，我们观察到单宁酸至少部分负责这种活性。本研究的目的是评估市售单宁酸的抗CXCL12/CXCR4活性，并评估其在体外抑制肿瘤细胞迁移和血管生成的潜力。
通过趋化性测定、配体结合测定和荧光激活细胞分选分析来测量单宁酸对CXCL12/CXCR4的抑制作用。通过体外内皮细胞管形成来评估单宁酸的抗血管生成作用。
在无毒浓度下，单宁酸特异性抑制CXCL12诱导的人单核细胞迁移（IC50，7.5μg/ml），但不抑制CCL2、CCL3、CCL5、甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）或C5a诱导的迁移。该化合物显著阻断CXCL12与THP-1细胞的结合（IC50，0.36μg/ml）。单宁酸还抑制CXCL12诱导的MDA 231乳腺肿瘤细胞迁移，但不抑制表皮生长因子诱导的迁移。此外，0.5μg/ml的单宁酸选择性抑制CXCL12介导的牛主动脉内皮细胞毛细管形成，但不抑制碱性成纤维细胞生长因子或内皮细胞生长补充剂介导的形成。
这些研究表明，单宁酸是一种新型的选择性CXCL12/CXCR4拮抗剂，因此可能为单宁酸报道的抗肿瘤和抗炎特性提供机制基础。
