Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.
Anticancer Drugs. 2013 Sep;24(8):781-91. doi: 10.1097/CAD.0b013e328362fb84.
Arctigenin, a functional ingredient of several traditional Chinese herbs, has been reported to have potential antitumor activity. However, its mechanisms of action are still not well elucidated. Because the establishment and metastatic spread of tumors is crucially dependent on angiogenesis, here we investigated whether arctigenin inhibits tumor growth by disturbing blood vessel formation. For this purpose, human dermal microvascular endothelial cells were exposed to different arctigenin doses to study their viability, proliferation, protein expression, migration, and tube formation compared with vehicle-treated controls. In addition, arctigenin action on vascular sprouting was analyzed in an aortic ring assay. Furthermore, we studied direct arctigenin effects on CT26.WT colon carcinoma cells. Spheroids of these tumor cells were transplanted into the dorsal skinfold chamber of arctigenin-treated and vehicle-treated BALB/c mice for the in-vivo analysis of tumor vascularization and growth by intravital fluorescence microscopy, histology, and immunohistochemistry. We found that noncytotoxic doses of arctigenin dose dependently reduced the proliferation of human dermal microvascular endothelial cells without affecting their migratory and tube-forming capacity. Arctigenin treatment also resulted in a decreased cellular expression of phosphorylated serine/threonine protein kinase AKT, vascular endothelial growth factor receptor 2, and proliferating cell nuclear antigen and inhibited vascular sprouting from aortic rings. In addition, proliferation, but not secretion of vascular endothelial growth factor, was decreased in arctigenin-treated tumor cells. Finally, arctigenin suppressed the vascularization and growth of engrafting CT26.WT tumors in the dorsal skinfold chamber model. Taken together, these results show for the first time an antiangiogenic action of arctigenin, which may contribute considerably toward its antitumor activity.
牛蒡子苷元是几种中草药的功能性成分，据报道具有潜在的抗肿瘤活性。然而，其作用机制仍未得到充分阐明。由于肿瘤的建立和转移扩散严重依赖于血管生成，因此我们研究了牛蒡子苷元是否通过干扰血管形成来抑制肿瘤生长。为此，将人真皮微血管内皮细胞暴露于不同剂量的牛蒡子苷元下，与对照溶剂处理组比较，研究其活力、增殖、蛋白表达、迁移和管腔形成。此外，还在主动脉环实验中分析了牛蒡子苷元对血管发芽的作用。此外，我们研究了牛蒡子苷元对 CT26.WT 结肠癌细胞的直接作用。这些肿瘤细胞的球体被移植到牛蒡子苷元处理和对照溶剂处理的 BALB/c 小鼠背部皮肤囊腔中，通过活体荧光显微镜、组织学和免疫组织化学分析肿瘤血管生成和生长。我们发现，非细胞毒性剂量的牛蒡子苷元依赖性地降低了人真皮微血管内皮细胞的增殖，而不影响其迁移和管腔形成能力。牛蒡子苷元处理还导致磷酸化丝氨酸/苏氨酸蛋白激酶 AKT、血管内皮生长因子受体 2 和增殖细胞核抗原的细胞表达减少，并抑制了主动脉环的血管发芽。此外，牛蒡子苷元处理降低了肿瘤细胞的增殖，但不影响血管内皮生长因子的分泌。最后，牛蒡子苷元抑制了背部皮肤囊腔模型中植入的 CT26.WT 肿瘤的血管生成和生长。总之，这些结果首次表明牛蒡子苷元具有抗血管生成作用，这可能对其抗肿瘤活性有重要贡献。
