Inhibition of Type I Interferon-Mediated Antiviral Action in Human Glioma Cells by the IKK Inhibitors BMS-345541 and TPCA-1
Inhibition of Type I Interferon-Mediated Antiviral Action in Human Glioma Cells by the IKK Inhibitors BMS-345541 and TPCA-1
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DOI：
10.1089/jir.2012.0002
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发表时间：
2012-08-01
影响因子：
2.3
通讯作者：
Pfeffer, Lawrence M.
中科院分区：
文献类型：
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作者：
Du, Ziyun;Whitt, Michael A.;Pfeffer, Lawrence M.
核因子κ B （NF κ B）信号转导通路在免疫、炎症、细胞生长和生存等方面发挥重要作用。由于该通路的失调导致各种癌症和免疫疾病中NF κ B的高组成性激活，因此针对该通路的特异性药物的开发已成为治疗这些疾病的焦点。NF κ B调节细胞对干扰素（IFN）反应的各个方面。然而，NF κ B信号通路的上游调节因子，κ B激酶（IKK）复合物的抑制剂，对IFN功能的作用尚未得到研究。在本研究中，我们检测了2种TICK抑制剂N-（1,8-二甲基咪唑[1,2-a]喹诺沙林-4-基）-1,2-乙二胺盐酸盐（BMS-345541）和2-[（氨基羰基）氨基]-5-（4-氟苯基）-3-噻吩甲酰胺（TPCA-1）对几种人类胶质瘤细胞系中IFN作用的影响。IKK抑制剂抑制胶质瘤细胞增殖，以及tnf诱导的RelA （p65）核易位和NF κ b依赖性IL8基因表达。重要的是，BMS-345541和TPCA-1对ifn诱导的基因表达有不同的抑制作用，完全抑制MX1和GBP1基因的表达，而对ISG15的表达只有轻微的影响。此外，这些IICK抑制剂在阻断ifn诱导的抗水疱性口炎病毒（VSV）和脑心肌炎病毒（EMCV）的细胞病变效应和复制方面表现出显著差异。我们的研究结果表明IICK复合物在ifn诱导的基因表达和抗病毒活性中起重要作用。由于VSV和EMCV是用于癌症治疗的溶瘤病毒，我们的研究结果表明TICK抑制剂与溶瘤病毒联合使用具有潜在的协同作用。
The nuclear factor-kappa B (NF kappa B) signal transduction pathway plays an important role in immunity, inflammation, cell growth, and survival. Since dysregulation of this pathway results in high, constitutive NF kappa B activation in various cancers and immune disorders, the development of specific drugs to target this pathway has become a focus for treating these diseases. NF kappa B regulates various aspects of the cellular response to interferon (IFN). However, the role of the upstream regulator of the NF kappa B signaling pathway, the inhibitor of kappa B kinase (IKK) complex, on IFN function has not been examined. In the present study, we examined the effects of 2 TICK inhibitors, N-(1,8-Dimethylimidazo[1,2-a]quinoxalin-4-yl)-1,2-ethanediamine hydrochloride (BMS-345541) and 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), on IFN action in several human glioma cell lines. IKK inhibitors inhibit glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NF kappa B-dependent IL8 gene expression. Importantly, BMS-345541 and TPCA-1 differentially inhibit IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression. Furthermore, these IICK inhibitors displayed marked differences in blocking IFN-induced antiviral action against cytopathic effects and replication of vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). Our results show that the IICK complex plays an important function in IFN-induced gene expression and antiviral activity. Since VSV and EMCV are oncolytic viruses used in cancer therapy, our results indicate the potential synergy in combining TICK inhibitors with oncolytic viruses.