Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer
Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer
复制标题
氯化两面针碱抑制 STAT3 信号通路抑制人胃癌血管生成和生长
DOI：
10.1158/1535-7163.mct-11-0648
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发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Liu, Mingyao
中科院分区：
文献类型：
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作者：
Chen, Jing;Wang, Jieqiong;Liu, Mingyao
STAT3与人类恶性肿瘤密切相关，而STAT3的结构性激活在细胞存活、血管生成、免疫逃避和炎症中起着至关重要的作用。在本研究中，我们证明了两面针碱氯是一种从两面针中提取的天然植物化学生物碱，它通过STAT3信号通路发挥强大的抗癌活性。氯化两面针碱在体外剂量依赖性地抑制血管内皮生长因子诱导的内皮细胞的增殖、迁移和管状结构的形成，并在体内显著减少血管内皮生长因子引发的小鼠角膜和Matrigel栓的新生血管形成。氯化两面针碱对血管生成的抑制作用可以通过抑制Janus激酶2/STAT3信号转导通路和抑制血管内皮细胞内STAT3DNA结合活性来解释。此外，氯化两面针碱能抑制人胃癌细胞中STAT3蛋白的表达，抑制其与DNA的结合活性，并抑制STAT3依赖的靶基因的表达，包括细胞周期蛋白D1、Bcl-xL和血管内皮生长因子。与早期研究结果一致，氯化两面针碱在体外抑制胃肿瘤细胞生长和诱导肿瘤细胞凋亡，并有效地抑制人SGC-7901胃实体瘤(n=8)的体积、重量和微血管密度(n=8)。免疫组织化学和Western印迹分析进一步表明，该生物碱能显著降低移植瘤中STAT3、CD31和VEGF蛋白的表达。综上所述，我们认为氯化两面针碱是一种很有前途的抗癌药物候选药物，是一种有效的STAT3信号抑制剂。摩尔癌症治疗；11(2)；277-87。©2011 AACR。
STAT3 has been strongly implicated in human malignancies, and constitutive activation of STAT3 serves a crucial role in cell survival, angiogenesis, immune evasion, and inflammation. In this study, we showed that nitidine chloride, a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb) DC, exerts potent anticancer activity through STAT3 signaling cascade. Nitidine chloride dose dependently suppressed VEGF-induced endothelial cell proliferation, migration, and tubular structure formation in vitro and dramatically reduced VEGF-triggered neovascularization in mouse cornea and Matrigel plugs in vivo. This angiogenesis inhibition mediated by nitidine chloride was well interpreted by the suppression of Janus kinase 2/STAT3 signaling and STAT3 DNA-binding activity in endothelial cells. Furthermore, nitidine chloride suppressed the constitutively activated STAT3 protein, its DNA-binding activity, and the expression of STAT3-dependent target genes, including cyclin D1, Bcl-xL, and VEGF in human gastric cancer cells. Consistent with the earlier findings, nitidine chloride inhibited gastric tumor cell growth and induced tumor cell apoptosis in vitro and effectively suppressed the volume, weight, and microvessel density of human SGC-7901 gastric solid tumors (n = 8) at a dosage of 7 mg/kg/d (intraperitoneal injection). Immunohistochemistry and Western blot analysis further revealed that the expression of STAT3, CD31, and VEGF protein in xenografts was remarkably decreased by the alkaloid. Taken together, we propose that nitidine chloride is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor. Mol Cancer Ther; 11(2); 277–87. ©2011 AACR.