1'-Acetoxychavicol acetate suppresses angiogenesis-mediated human prostate tumor growth by targeting VEGF-mediated Src-FAK-Rho GTPase-signaling pathway.
1'-Acetoxychavicol acetate suppresses angiogenesis-mediated human prostate tumor growth by targeting VEGF-mediated Src-FAK-Rho GTPase-signaling pathway.
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DOI：
10.1093/carcin/bgr052
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发表时间：
2011-06
期刊：
影响因子：
4.7
通讯作者：
Xiufeng Pang;Li Zhang;Li Lai;Jing Chen;Yuanyuan Wu;Zhengfang Yi;Jian Zhang;W. Qu;B. Aggarwal-B.
中科院分区：
文献类型：
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作者：
Xiufeng Pang;Li Zhang;Li Lai;Jing Chen;Yuanyuan Wu;Zhengfang Yi;Jian Zhang;W. Qu;B. Aggarwal-B.
迫切需要安全、有效和负担得起的癌症治疗剂。我们描述了1'-acetoxychavicol acetate (ACA)，暹罗姜（Languas galanga）的一种成分，可以通过很大程度上废除血管生成来抑制前列腺肿瘤的生长。ACA以剂量依赖的方式抑制原代培养人脐血管内皮细胞（HUVECs）的增殖、迁移、粘附和小管形成。ACA还能在体外抑制vegf诱导的主动脉环微血管的萌发，并在体内抑制基质塞中新血管的形成。我们进一步证明了这种chavicol的机制是阻断vegf介导的Src激酶、局灶黏附激酶（FAK）和Rho家族的小鸟苷三磷酸酶（GTPases） （Rac1和Cdc42，而不是RhoA）在HUVECs中的激活。此外，用ACA治疗人前列腺癌细胞（PC-3）导致细胞活力下降，并通过干扰双Src/FAK激酶抑制血管生成因子的产生。给人前列腺癌PC-3异种移植瘤小鼠皮下注射ACA （6 mg/kg/天）后，可显著抑制肿瘤体积和肿瘤重量，降低Src、CD31、VEGF和Ki-67水平。免疫组织化学和TUNEL分析显示，aca处理的小鼠肿瘤微血管密度和细胞增殖也明显受到抑制。综上所述，我们的研究结果表明ACA靶向Src-FAK-Rho GTPase通路，从而抑制前列腺肿瘤血管生成和生长。
Cancer therapeutic agents that are safe, effective and affordable are urgently needed. We describe that 1'-acetoxychavicol acetate (ACA), a component of Siamese ginger (Languas galanga), can suppress prostate tumor growth by largely abrogating angiogenesis. ACA suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, adhesion and tubulogenesis of primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. ACA also inhibited VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed new vasculature formation in Matrigel plugs in vivo. We further demonstrated that the mechanisms of this chavicol were to block the activation of VEGF-mediated Src kinase, focal adhesion kinase (FAK) and Rho family of small guanosine triphosphatases (GTPases) (Rac1 and Cdc42 but not RhoA) in HUVECs. Furthermore, treatment of human prostate cancer cells (PC-3) with ACA resulted in decreased cell viability and suppression of angiogenic factor production by interference with dual Src/FAK kinases. After subcutaneous administration to mice bearing human prostate cancer PC-3 xenografts, ACA (6 mg/kg/day) remarkably inhibited tumor volume and tumor weight and decreased levels of Src, CD31, VEGF and Ki-67. As indicated by immunohistochemistry and TUNEL analysis, microvessel density and cell proliferation were also dramatically suppressed in tumors from ACA-treated mice. Taken together, our findings suggest that ACA targets the Src-FAK-Rho GTPase pathway, leading to the suppression of prostate tumor angiogenesis and growth.