A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors
A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors
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DOI：
10.1073/pnas.2235846100
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发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Segal, RA
中科院分区：
文献类型：
--
作者：
Rubin, JB;Kung, AL;Segal, RA
成人的绝大多数脑肿瘤呈现神经胶质特性。儿童脑肿瘤多种多样：许多具有神经元特性，而其他一些则具有神经胶质特征。在此我们表明，G(i)蛋白偶联受体CXCR4的激活对于恶性神经元肿瘤和神经胶质肿瘤的生长都至关重要。系统性给予CXCR4拮抗剂AMD3100通过增加细胞凋亡和减少肿瘤细胞增殖来抑制颅内胶质母细胞瘤和髓母细胞瘤异种移植物的生长。这反映了AMD3100降低细胞外信号调节激酶1和2以及Akt激活的能力，这些都是CXCR4下游促进存活、增殖和迁移的通路。这些研究（i）证明CXCR4对多种脑恶性肿瘤的进展至关重要，并且（ii）为临床评估AMD3100治疗成人和儿童恶性脑肿瘤提供了科学依据。
The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the G(i) protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.