Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model.
Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model.
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DOI：
10.1111/j.1538-7836.2009.03553.x
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Monteiro RQ
中科院分区：
文献类型：
--
作者：
Carneiro-Lobo TC;Konig S;Machado DE;Nasciutti LE;Forni MF;Francischetti IM;Sogayar MC;Monteiro RQ
凝血引发蛋白组织因子（TF）的表达水平与胶质瘤患者血管密度和组织学恶性分级相关。高级别肿瘤（胶质母细胞瘤）中促凝剂张力的增加也表明TF在该疾病进展中的潜在作用，并提示抗凝剂可作为治疗的佐剂。我们假设用蜱抗凝剂Ixolaris阻断TF活性可能会干扰胶质母细胞瘤的进展。通过流式细胞术和功能测定（外源性张力酶）在U87-MG细胞中鉴定出TF。此外，流式细胞分析显示，暴露在U87-MG细胞表面的磷脂酰丝氨酸支持内在张力酶（FIXa/ fviia /FX）和凝血酶原（FVa/FXa/凝血酶原）复合物的组装，分别导致FXa和凝血酶的产生。Ixolaris可有效阻断U87-MG人胶质母细胞瘤细胞株体外tgf依赖性促凝活性，并可减弱多分子凝血复合物的组装。值得注意的是，Ixolaris抑制了裸鼠体内U87-MG细胞的致瘤潜能，没有观察到出血。这种对肿瘤生长的抑制作用与VEGF的下调和肿瘤血管化的减少有关。本研究结果提示，Ixolaris可能是一种很有前景的抗人胶质母细胞瘤药物。
The expression levels of the clotting initiator protein Tissue Factor (TF) correlates with vessel density and the histological malignancy grade of glioma patients. Increased procoagulant tonus in high grade tumors (glioblastomas) also indicate a potential role for TF in progression of this disease, and suggest that anticoagulants could be used as adjuvants for its treatment. We hypothesized that blocking of TF activity with the tick anticoagulant Ixolaris might interfere with glioblastoma progression. TF was identified in U87-MG cells by flow-cytometric and functional assays (extrinsic tenase). In addition, flow-cytometric analysis demonstrated the exposure of phosphatidylserine in the surface of U87-MG cells which supported the assembly of intrinsic tenase (FIXa/FVIIIa/FX) and prothrombinase (FVa/FXa/prothrombin) complexes, accounting for the production of FXa and thrombin, respectively. Ixolaris effectively blocked the in vitro TF-dependent procoagulant activity of U87-MG human glioblastoma cell line and attenuated multimolecular coagulation complexes assembly. Notably, Ixolaris inhibited in vivo tumorigenic potential of U87-MG cells in nude mice, without observable bleeding. This inhibitory effect of Ixolaris on tumor growth was associated with downregulation of VEGF and reduced tumor vascularization. Our results suggest that Ixolaris might be a promising agent for anti-tumor therapy of human glioblastoma.
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影响因子：
11.5
作者：
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3.1
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