Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model

被引：72

作者：

Carneiro-Lobo, T. C.

Konig, S. ^{[2
]}

Machado, D. E. ^{[3
]}

Nasciutti, L. E. ^{[3
]}

Forni, M. F. ^{[4
]}

Francischetti, I. M. B. ^{[5
]}

Sogayar, M. C. ^{[4
]}

Monteiro, R. Q. ^{[1
]}

机构：

[1] Univ Fed Rio de Janeiro, CCS, Inst Bioquim Med, BR-21941590 Rio de Janeiro, Brazil

[2] Univ Fed Rio de Janeiro, Dept Anat, BR-21941590 Rio de Janeiro, Brazil

[3] Univ Fed Rio de Janeiro, Dept Histol & Embriol, BR-21941590 Rio de Janeiro, Brazil

[4] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-01498 Sao Paulo, Brazil

[5] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA

来源：

JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2009年 / 7卷 / 11期

基金：

巴西圣保罗研究基金会;

关键词：

angiogenesis; anticoagulant therapy; glioblastoma; Ixolaris; primary tumor growth; tissue factor; FACTOR PATHWAY INHIBITOR; FACTOR EXPRESSION; FACTOR-XA; MOLECULAR-MECHANISMS; BLOOD-COAGULATION; POTENT INHIBITOR; CANCER; THROMBIN; NECROSIS; HYPOXIA;

D O I：

10.1111/j.1538-7836.2009.03553.x

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: The expression levels of the clotting initiator protein Tissue Factor (TF) correlate with vessel density and the histological malignancy grade of glioma patients. Increased procoagulant tonus in high grade tumors (glioblastomas) also indicates a potential role for TF in progression of this disease, and suggests that anticoagulants could be used as adjuvants for its treatment. Objectives: We hypothesized that blocking of TF activity with the tick anticoagulant Ixolaris might interfere with glioblastoma progression. Methods and results: 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 the U87-MG human glioblastoma cell line and attenuated multimolecular coagulation complexes assembly. Notably, Ixolaris inhibited the 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. Conclusion: Our results suggest that Ixolaris might be a promising agent for anti-tumor therapy in humans.

引用

页码：1855 / 1864

页数：10

共 55 条

[1] Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor [J].