一直以來某些植物化學物質包括多酚類物質如黃酮類化合物被認為具有抗癌功效,。近日，一新研究證實這些化合物通過抑制腫瘤血管生成發(fā)揮其保護作用,。新研究中發(fā)現(xiàn)一種植物化學物質具有潛在的抗血管生成活性，這不僅對了解這些化合物預防腫瘤的作用機制,，同時也為開發(fā)新的腫瘤治療試劑鋪平了道路,。
在試圖找出能降低癌癥發(fā)病率和死亡率的植物化學物質的道路上，研究人員篩選出了一套迄今未經研究過的植物雌激素的代謝產物,。在這項新研究中,，科學家展示了一種新的植物雌激素——6-甲氧基雌馬酚（6-ME）能抑制血管內皮生長因子誘導的人臍靜脈內皮細胞（HUVE）細胞增殖，而血管內皮生長因子誘導的HUVE細胞遷移和生存不受影響,。此外6-ME抑制FGF-2誘導的牛腦微血管內皮細胞（BBCE）的增殖,。
6-ME主要通過抑制血管內皮生長因子誘導的ERK1/2磷酸化,，ERK1/2磷酸化調控血管內皮生長因子誘導的內皮細胞增殖的關鍵級聯(lián)反應,。在此背景下,，6-ME對MEK1/2的抑制效應呈劑量依賴性，MEK1/2是唯一已知的激活ERK1/2磷酸化的上游效應分子,。6-ME并沒有改變血管內皮生長因子誘導的p38 MAPK或AKT的磷酸化,，對VEGF誘導的血管內皮細胞遷移和存活無影響。A-431移植瘤腫瘤周圍注入6-ME能減少腫瘤的生長,、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，這兩者是有絲分裂MAPK通路的兩個關鍵部件,，進而抑制血管內皮生長因子,、FGF2誘導的內皮細胞增殖。A-431移植瘤小鼠注射6-ME后新生血管和腫瘤體積減少,，研究結果提示6-ME可以被開發(fā)一種新型的抗血管生成劑治療癌癥,。（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.
