Tumor anti-angiogenic effect and mechanism of action of delta-tocotrienol.
Tumor anti-angiogenic effect and mechanism of action of delta-tocotrienol.
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DOI：
10.1016/j.bcp.2008.05.017
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发表时间：
2008-08
影响因子：
5.8
通讯作者：
Akira Shibata;K. Nakagawa;Phumon Sookwong;T. Tsuzuki;S. Oikawa;T. Miyazawa
中科院分区：
文献类型：
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作者：
Akira Shibata;K. Nakagawa;Phumon Sookwong;T. Tsuzuki;S. Oikawa;T. Miyazawa
由药物和食物成分介导的抗血管生成治疗是癌症预防的既定策略。我们之前的细胞培养研究发现了一种食物来源的抗血管生成化合物，生育三烯醇（T3，一种不饱和维生素E），作为一种潜在的血管生成抑制剂。在T3异构体中，δ-T3被认为是最有效的化合物。因此，本研究的目的是评估δ-T3对肿瘤血管生成的抑制作用。由于生长因子（如血管内皮生长因子和成纤维细胞生长因子）在肿瘤血管生成中起关键作用，因此使用从人结直肠癌细胞中提取的富含这些生长因子的条件培养基（DLD-1-CM）作为血管生成刺激。δ-T3 （2.5 ~ 5μ m）显著抑制dld -1- cm诱导的人脐静脉内皮细胞形成、迁移和粘附。这些效应部分与δ-T3产生的活性氧有关。Western blot分析显示，δ-T3的抗血管生成作用与调节生长因子依赖性磷脂酰肌醇-3激酶(PI3K)/磷酸肌醇依赖性蛋白激酶(PDK)/Akt信号通路以及诱导内皮细胞的应激反应有关。此外，我们进行了小鼠体内Matrigel塞血管生成实验，发现δ-T3 （10-20μg）对dld -1诱导的血管形成具有剂量依赖性的抑制作用。这些结果表明，T3有可能作为一种治疗性膳食补充剂，以减少肿瘤血管生成。
Anti-angiogenic therapy mediated by drugs and food components is an established strategy for cancer prevention. Our previous cell-culture studies identified a food-derived anti-angiogenic compound, tocotrienol (T3, an unsaturated vitamin E), as a potential angiogenic inhibitor. Among T3 isomers, δ-T3 is considered as the most potent compound. The purpose of this study was therefore to evaluate the inhibitory effect of δ-T3 on tumor angiogenesis. As growth factors (e.g., vascular endothelial growth factor and fibroblast growth factor) play critical roles in tumor angiogenesis, a conditioned medium rich in these growth factors from human colorectal adenocarcinoma cells (DLD-1-CM) was used as an angiogenic stimulus. δ-T3 (2.5–5μM) significantly suppressed DLD-1-CM-induced tube formation, migration, and adhesion on human umbilical vein endothelial cells. These effects were partly associated with reactive oxygen species generation by δ-T3. Western blot analysis revealed that the anti-angiogenic effect of δ-T3 is attributable to regulation of growth factor-dependent phosphatidylinositol-3 kinase (PI3K)/phosphoinositide-dependent protein kinase (PDK)/Akt signaling as well as to induction stress response in endothelial cells. Moreover, we conducted an in vivo mouse Matrigel plug angiogenesis assay, and found that δ-T3 (10–20μg) exhibits dose-dependent inhibition of DLD-1-induced vessel formation. These results suggest that T3 has potential use as a therapeutic dietary supplement for minimizing tumor angiogenesis.