Medical Oncology, 2012, 29(1):349-57.

Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation

Xiaoping Yu, Jundong Zhu, Mantian Mi, et al

School of Public Health Chengdu Medical College Chengdu China; Department of Burn Injury and Plastic Surgery, The First Affiliated Hospital Chengdu Medical College Chengdu China; Department of Nutrition and Food Hygiene, School of Preventive MedicineThe Third Military Medical University Chongqing China

Genistein (Gen), a soy isoflavone, is considered to exert potent antitumor effect partially through its anti-angiogenesis property. However, the precise molecular mechanism is still unknown. Our previous investigations have demonstrated that genistein down-regulates expression of pro-angiogenic factors via inhibiting protein tyrosine kinase (PTK) activity both in breast cancer cells and in xenograft tumors. In the present experiment, we chose cultured human umbilical vein endothelial cells (HUVECs), which have a considerable role in tumor angiogenesis formation, to explore the influence of genistein on VEGF-stimulated endothelial cell activation and the underlying mechanism. Stimulation of human primary HUVECs by VEGF not only increased endothelial cell protein tyrosine kinase (PTK) activity but also augmented matrix metalloproteinase-2 (MMP-2), -9 secretions and increased MMP-2, -9 activities. Treatment of ECs with genistein induced VEGF-loaded endothelial apoptosis by inhibiting production and activity of matrix metalloproteinases (MMPs). In addition, exposure to genistein decreased activation of JNK and p38, not ERK-1/2, induced by VEGF. Collectively, our findings suggested that the inhibition of PTK activity and MAPK activation and the decrease in MMPs production and activity by genistein interrupt VEGF-stimulated endothelial cell activation, which thereby may represent a mechanism that would explain the anti-angiogenesis effect of genistein and its cancer-protective function.

美国《医药肿瘤学》，2012年3月

抗血管生成的金雀异黄素通过降低PTK活性和 MAPK 活化抑制 VEGF 诱导的内皮细胞活化

于小平，朱骏东，米漫天，等

中国成都公共健康医学院；成都医学院第一附属医院烧伤和整形手术科；重庆第三军医大学预防医学院营养与食品卫生系

金雀异黄素 （Gen），一种大豆异黄酮，被认为部分通过抗血管生成属性可以发挥强大的抗肿瘤作用。然而，精确的分子机制目前仍不清楚。我们以前的探究表明，在异种移植肿瘤和乳腺癌细胞中金雀异黄素下调促血管生成分子的表达通过抑制蛋白酪氨酸激酶 (PTK) 活性。在本实验中，我们选择了体外培养的人体脐带静脉内皮细胞 (Huvec)，对肿瘤血管形成具有相当大的作用，来探讨金雀异黄素对 VEGF 刺激的内皮细胞活化和基本机制的影响。VEGF刺激人体原发性 Huvec 细胞基因不仅增加内皮细胞蛋白酪氨酸激酶 (PTK) 的活性而且拓宽了基质金属蛋白酶-2 (MMP-2)，-9 分泌物并增强了基质金属蛋白酶-2，-9 的活性。用金雀异黄素治疗ECs通过抑制基质金属蛋白酶 (MMPs) 的产生和活性诱导了VEGF 负载的内皮细胞凋亡。此外，接触金雀异黄素降低了 JNK 和 p38的活性，但不包括被VEGF诱导的ERK 1/2。总之，我们的研究结果认为金雀异黄素抑制酪氨酸激酶的活性，激活 MAPK以及降低MMPs的产生和活性，中断了 VEGF 刺激的内皮细胞活化，从而可能代表一种机制，可以解释金雀异黄素的抗血管生成作用以及防癌功效。