一直以来某些植物化学物质包括多酚类物质如黄酮类化合物被认为具有抗癌功效。近日，一新研究证实这些化合物通过抑制肿瘤血管生成发挥其保护作用。新研究中发现一种植物化学物质具有潜在的抗血管生成活性，这不仅对了解这些化合物预防肿瘤的作用机制，同时也为开发新的肿瘤治疗试剂铺平了道路。
在试图找出能降低癌症发病率和死亡率的植物化学物质的道路上，研究人员筛选出了一套迄今未经研究过的植物雌激素的代谢产物。在这项新研究中，科学家展示了一种新的植物雌激素——6-甲氧基雌马酚（6-ME）能抑制血管内皮生长因子诱导的人脐静脉内皮细胞（HUVE）细胞增殖，而血管内皮生长因子诱导的HUVE细胞迁移和生存不受影响。此外6-ME抑制FGF-2诱导的牛脑微血管内皮细胞（BBCE）的增殖。
6-ME主要通过抑制血管内皮生长因子诱导的ERK1/2磷酸化，ERK1/2磷酸化调控血管内皮生长因子诱导的内皮细胞增殖的关键级联反应。在此背景下，6-ME对MEK1/2的抑制效应呈剂量依赖性，MEK1/2是唯一已知的激活ERK1/2磷酸化的上游效应分子。6-ME并没有改变血管内皮生长因子诱导的p38 MAPK或AKT的磷酸化，对VEGF诱导的血管内皮细胞迁移和存活无影响。A-431移植瘤肿瘤周围注入6-ME能减少肿瘤的生长、抑制新生血管。
6-ME靶向作用于MEK1/2的磷酸化及其下游底物ERK1/2，这两者是有丝分裂MAPK通路的两个关键部件，进而抑制血管内皮生长因子、FGF2诱导的内皮细胞增殖。A-431移植瘤小鼠注射6-ME后新生血管和肿瘤体积减少，研究结果提示6-ME可以被开发一种新型的抗血管生成剂治疗癌症。（生物谷：Bioon.com）
doi:10.1186/1476-4598-11-35
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The isoflavone metabolite 6-methoxyequol inhibits angiogenesis and suppresses tumor growth
Sofia Bellou, Evdoxia Karali, Eleni Bagli, Nawaf Al-Maharik, Lucia Morbidelli, Marina Ziche, Herman Adlercreutz, Carol Murphy and Theodore Fotsis
Background
Increased consumption of plant-based diets has been linked to the presence of certain phytochemicals, including polyphenols such as flavonoids. Several of these compounds exert their protective effect via inhibition of tumor angiogenesis. Identification of additional phytochemicals with potential antiangiogenic activity is important not only for understanding the mechanism of the preventive effect, but also for developing novel therapeutic interventions.
Results
In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have screened a set of hitherto untested phytoestrogen metabolites concerning their anti-angiogenic effect, using endothelial cell proliferation as an end point. Here, we show that a novel phytoestrogen, 6-methoxyequol (6-ME), inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVE) cells, whereas VEGF-induced migration and survival of HUVE cells remained unaffected. In addition, 6-ME inhibited FGF-2-induced proliferation of bovine brain capillary endothelial (BBCE) cells. In line with its role in cell proliferation, 6-ME inhibited VEGF-induced phosphorylation of ERK1/2 MAPK, the key cascade responsible for VEGF-induced proliferation of endothelial cells. In this context, 6-ME inhibited in a dose dependent manner the phosphorylation of MEK1/2, the only known upstream activator of ERK1/2. 6-ME did not alter VEGF-induced phosphorylation of p38 MAPK or AKT, compatible with the lack of effect on VEGF-induced migration and survival of endothelial cells. Peri-tumor injection of 6-ME in A-431 xenograft tumors resulted in reduced tumor growth with suppressed neovasularization compared to vehicle controls (P < 0.01).
Conclusions
6-ME inhibits VEGF- and FGF2-induced proliferation of ECs by targeting the phosphorylation of MEK1/2 and it downstream substrate ERK1/2, both key components of the mitogenic MAPK pathway. Injection of 6-ME in mouse A-431 xenograft tumors results to tumors with decreased neovascularization and reduced tumor volume suggesting that 6-ME may be developed to a novel anti-angiogenic agent in cancer treatment.
