Chen Yi, Zhang Yi-Xiang, Li Mei-Hong, Zhao Wei-Min, Shi Yu-Hua, Miao Ze-Hong, Zhang Xiong-Wen, Lin Li-Ping, Ding Jian
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, Shanghai, PR China.
Biochem Biophys Res Commun. 2005 Apr 22;329(4):1334-42. doi: 10.1016/j.bbrc.2005.02.115.
The fungus Shiraia bambusicola yields the phytochemical 11,11'-dideoxyverticillin, which has been shown to possess potent anticancer activity both in vitro and in vivo. In this study, we reveal that 11,11'-dideoxyverticillin has anti-angiogenic activities and explore the potential mechanisms for this effect. Treatment with 11,11'-dideoxyverticillin inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) with IC(50) values of 0.17+/-0.05muM for VEGF-stimulated cells and 0.39+/-0.08muM for serum-stimulated cells. 11,11'-Dideoxyverticillin also antagonized the antiapoptotic effects of VEGF on serum-deprived HUVECs, inhibited VEGF-induced HUVEC migration in vitro, and blocked serum-induced HUVEC tube formation. Moreover, 11,11'-dideoxyverticillin completely blocked VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice. In addition, 11,11'-dideoxyverticillin decreased VEGF secretion by MDA-MB-468 breast cancer cells, and significantly suppressed VEGF-induced tyrosine phosphorylation of Flt-1 and KDR/Flk-1. This inhibition of receptor phosphorylation was correlated with a marked decrease in VEGF-triggered pERK activation and a dramatic increase in pP38 MAPK, but no apparent change in pAkt. Together, these findings strongly suggest that 11,11'-dideoxyverticillin is a structurally novel angiogenesis inhibitor.
竹黄真菌可产生植物化学物质11,11'-二脱氧轮枝菌素，该物质已被证明在体外和体内均具有强大的抗癌活性。在本研究中，我们揭示了11,11'-二脱氧轮枝菌素有抗血管生成活性，并探讨了这种作用的潜在机制。用11,11'-二脱氧轮枝菌素处理可抑制人脐静脉内皮细胞（HUVECs）的增殖，对于VEGF刺激的细胞，IC(50)值为0.17±0.05μM，对于血清刺激的细胞，IC(50)值为0.39±0.08μM。11,11'-二脱氧轮枝菌素还可拮抗VEGF对血清饥饿的HUVECs的抗凋亡作用，在体外抑制VEGF诱导的HUVEC迁移，并阻断血清诱导的HUVEC管形成。此外，11,11'-二脱氧轮枝菌素可完全阻断VEGF诱导的基质胶包埋的大鼠主动脉环微血管芽生和小鼠基质胶栓中的血管生长。另外，11,11'-二脱氧轮枝菌素可降低MDA-MB-468乳腺癌细胞分泌VEGF，并显著抑制VEGF诱导的Flt-1和KDR/Flk-1酪氨酸磷酸化。这种对受体磷酸化的抑制与VEGF触发的pERK激活的显著降低和pP38 MAPK的显著增加相关，但pAkt无明显变化。总之，这些发现强烈表明11,11'-二脱氧轮枝菌素是一种结构新颖的血管生成抑制剂。
