Therapeutic potential of AZD1480 for the treatment of human glioblastoma.
Therapeutic potential of AZD1480 for the treatment of human glioblastoma.
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DOI：
10.1158/1535-7163.mct-11-0480
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发表时间：
2011-12
影响因子：
5.7
通讯作者：
Benveniste EN
中科院分区：
文献类型：
--
作者：
McFarland BC;Ma JY;Langford CP;Gillespie GY;Yu H;Zheng Y;Nozell SE;Huszar D;Benveniste EN
Janus激酶（JAK）/转录信号激活因子（STAT）通路的异常激活与胶质母细胞瘤（GBM）进展有关。为了开发抑制STAT-3信号传导的治疗策略，我们评估了JAK 1和JAK 2的药理学抑制剂AZD 1480的作用。在这项研究中，在人类和小鼠胶质瘤细胞系中测试了AZD 1480的体外疗效。AZD 1480治疗有效地阻断了人和鼠胶质瘤细胞中的组成性和刺激诱导的JAK 1、JAK 2和STAT-3磷酸化，并导致细胞增殖减少和诱导凋亡。此外，我们利用人异种移植GBM样品作为体内JAK/STAT-3信号传导研究的模型，因为在裸鼠中作为异种移植物繁殖的人GBM样品保留了体内观察到的标志性遗传改变和侵袭性表型。在这些异种移植肿瘤中，JAK 2和STAT-3是组成性活性的，但在肿瘤之间水平不同，这与GBM的异质性一致。AZD 1480在体外抑制这些GBM异种移植肿瘤中JAK 2和STAT-3的组成性和刺激诱导的磷酸化、下游基因表达并抑制细胞增殖。此外，AZD 1480抑制GBM肿瘤中神经胶质瘤起始细胞群中的STAT-3活化。在体内，AZD 1480通过抑制STAT-3活性抑制皮下肿瘤的生长，并增加携带颅内GBM肿瘤的小鼠的存活率，这表明在GBM肿瘤患者的治疗研究中应考虑AZD 1480对JAK/STAT-3通路的药理学抑制。
Aberrant activation of the Janus Kinase (JAK)/Signal Activator of Transcription (STAT) pathway has been implicated in glioblastoma (GBM) progression. To develop a therapeutic strategy to inhibit STAT-3 signaling, we have evaluated the effects of AZD1480, a pharmacological inhibitor of JAK1 and JAK2. In this study, the in vitro efficacy of AZD1480 was tested in human and murine glioma cell lines. AZD1480 treatment effectively blocks constitutive and stimulus-induced JAK1, JAK2 and STAT-3 phosphorylation in both human and murine glioma cells, and leads to a decrease in cell proliferation and induction of apoptosis. Furthermore, we utilized human xenograft GBM samples as models for the study of JAK/STAT-3 signaling in vivo, since human GBM samples propagated as xenografts in nude mice retain both the hallmark genetic alterations and the invasive phenotype seen in vivo. In these xenograft tumors, JAK2 and STAT-3 are constitutively active, but levels vary among tumors, which is consistent with the heterogeneity of GBMs. AZD1480 inhibits constitutive and stimulus-induced phosphorylation of JAK2 and STAT-3 in these GBM xenograft tumors in vitro, downstream gene expression and inhibits cell proliferation. Furthermore, AZD1480 suppresses STAT-3 activation in the glioma-initiating cell population in GBM tumors. In vivo, AZD1480 inhibits the growth of subcutaneous tumors and increases survival of mice bearing intracranial GBM tumors by inhibiting STAT-3 activity, indicating that pharmacological inhibition of the JAK/STAT-3 pathway by AZD1480 should be considered for study in the treatment of patients with GBM tumors.