Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12.
Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12.
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DOI：
10.1371/journal.pone.0035513
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Houghton PJ
中科院分区：
文献类型：
--
作者：
Bid HK;Oswald D;Li C;London CA;Lin J;Houghton PJ
最近的数据表明，信号转导和转录激活因子3（STAT 3）途径是各种类型癌症中VEGF产生和血管生成所必需的。STAT 3抑制剂已显示降低肿瘤中的肿瘤微血管密度，但尚未描述直接的抗血管生成活性。我们研究了STAT 3小分子抑制剂（LLL 12）在体外人脐带血管内皮细胞（HUVEC）、体内血管生成Matrigel模型中的直接作用，以及其在骨肉瘤异种移植模型中的抗肿瘤活性。LLL 12（100 nM）显著抑制HUVEC中VEGF刺激的STAT 3磷酸化，降低其增殖/迁移并抑制VEGF诱导的管形成。LLL 12处理的HUVEC的形态学分析显示肌动蛋白/微管蛋白分布和成束的显著变化。在scid小鼠中，LLL 12以每天5 mg/kg的剂量将微血管侵入VEGF灌注的基质胶塞减少了约90%。肿瘤进展一段时间（2周）后，LLL 12完全抑制了已建立的OS-1骨肉瘤异种移植物的进一步生长。药效学研究显示在对照肿瘤中稳健的磷酸化STAT 3，而在LLL 12处理的OS-1肿瘤中未检测到磷酸化-STAT 3。与对照组相比，经治疗的肿瘤表现出增殖降低（Ki 67染色）和微血管密度降低（CD 34染色），但凋亡无显著增加（TUNEL染色）。使用抗体阵列的血管生成因子的测定显示，与对照肿瘤相比，LLL 12处理的肿瘤中VEGF、MMP-9、血管生成素12、组织因子和FGF-1表达显著降低。这些发现提供了LLL 12在体外和体内有效抑制肿瘤血管生成的第一个证据。
Recent data indicate the Signal Transducer and Activator of Transcription 3 (STAT3) pathway is required for VEGF production and angiogenesis in various types of cancers. STAT3 inhibitors have been shown to reduce tumor microvessel density in tumors but a direct anti-angiogenic activity has not been described. We investigated the direct action of a small molecule inhibitor of STAT3 (LLL12) in human umbilical cord vascular endothelial cells (HUVECs) in vitro, in a Matrigel model for angiogenesis in vivo, and its antitumor activity in a xenograft model of osteosarcoma. LLL12 (100 nM) significantly inhibited VEGF-stimulated STAT3 phosphorylation in HUVECs, reduced their proliferation/migration and inhibited VEGF-induced tube formation. Morphologic analysis of LLL12 treated HUVECs demonstrated marked changes in actin/tubulin distribution and bundling. In scid mice, LLL12 reduced microvessel invasion into VEGF-infused Matrigel plugs by ∼90% at a dose of 5 mg/kg daily. Following a period of tumor progression (2 weeks), LLL12 completely suppressed further growth of established OS-1 osteosarcoma xenografts. Pharmacodynamic studies showed robust phosphorylated STAT3 in control tumors, whereas phospho-STAT3 was not detected in LLL12-treated OS-1 tumors. Treated tumors demonstrated decreased proliferation (Ki67 staining), and decreased microvessel density (CD34 staining), but no significant increase in apoptosis (TUNEL staining), relative to controls. Assay of angiogenic factors, using an antibody array, showed VEGF, MMP-9, Angiopoietin1/2, Tissue Factor and FGF-1 expression were dramatically reduced in LLL12-treated tumors compared to control tumors. These findings provide the first evidence that LLL12 effectively inhibits tumor angiogenesis both in vitro and in vivo.
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影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
影响因子：
4.8
作者：
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DOI：
10.1073/pnas.0404100101
发表时间：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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