Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.
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DOI：
10.1158/0008-5472.can-09-0755
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Pang X;Yi Z;Zhang X;Sung B;Qu W;Lian X;Aggarwal BB;Liu M
血管生成在肿瘤生长和转移中的作用已得到充分证实。在药物开发中，鉴定阻断肿瘤血管生成并且是安全和可负担的小分子一直是一个挑战。在这项研究中，我们证明了乙酰基-11-酮-β-乳香酸（AKBA），一种来自印度草药植物（乳香）的活性成分，可以强烈抑制肿瘤血管生成。在实体瘤达到约100 mm 3后，AKBA抑制了每天治疗（10 mg/kg AKBA）的人前列腺肿瘤异种移植小鼠的肿瘤生长（n=5）。AKBA对肿瘤生长的抑制作用与抑制血管生成密切相关。当检查分子机制时，我们发现AKBA在小鼠的基质胶塞试验中显著抑制血管形成，并在大鼠离体主动脉环试验中有效抑制血管内皮生长因子（VEGF）诱导的微血管出芽。此外，AKBA抑制VEGF诱导的细胞增殖，趋化运动，并从原代培养的人脐血管内皮细胞（HUVECs）的毛细血管样结构的形成，以剂量依赖性的方式。Western blot分析和体外激酶活性测定显示AKBA抑制VEGF诱导的VEGF受体2激酶（KDR/Flk-1）磷酸化，IC 50为1.68 μmol/L。具体而言，AKBA抑制VEGFR 2的下游蛋白激酶，包括Src家族激酶、粘着斑激酶、细胞外信号相关激酶、AKT、mTOR和核糖体蛋白S6激酶。我们的研究结果表明，AKBA通过抑制VEGFR 2信号通路诱导的血管生成，有效地抑制人类前列腺肿瘤的生长。
The role of angiogenesis in tumor growth and metastasis is well established. Identification of small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we demonstrated that acetyl-11-keto-β-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg of AKBA) after solid tumors reached about 100 mm3 (n=5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively and suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 kinase (KDR/Flk-1) with IC50 of 1.68 μmol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mTOR, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.