HDAC inhibition amplifies gap junction communication in neural progenitors:: Potential for cell-mediated enzyme prodrug therapy
HDAC inhibition amplifies gap junction communication in neural progenitors:: Potential for cell-mediated enzyme prodrug therapy
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DOI：
10.1016/j.yexcr.2007.05.004
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发表时间：
2007-08-01
影响因子：
3.7
通讯作者：
Ekstrom, Tomas J.
中科院分区：
文献类型：
--
作者：
Khan, Zahidul;Akhtar, Monira;Ekstrom, Tomas J.
使用神经祖细胞（NPC）作为递送载体的酶前药疗法已应用于神经胶质瘤的动物模型中，并且依赖于递送和靶细胞之间的间隙连接通讯（GJC）。本研究探讨了组蛋白去乙酰化酶（HDAC）抑制剂对GJC的影响，目的是促进治疗分子从重组NPC转移。我们研究了一种新的永生化中脑细胞系，NGC-407的胚胎人起源具有神经前体的特征，作为一个潜在的交付车辆。用免疫印迹和免疫细胞化学方法检测细胞间隙连接蛋白43（Cx43）的表达。虽然未处理的分化中的NGC-407细胞中的Cx 43水平降低，但HDAC抑制剂4-苯基丁酸酯（4-PB）增加了增殖和分化细胞中的Cx 43表达沿着增加的膜沉积。同时，Ser 279/282-磷酸化形式的Cx43在两种培养条件下由4-PB下降。用HNSC 100人神经前体细胞和曲古抑菌素A验证了4-PB对NGC-407细胞的作用。改善功能性GJC对于涉及低分子量化合物的细胞间转运的治疗策略至关重要。我们在这里显示增强4-PB，功能GJC之间的NGC-407细胞，以及NGC-407和人神经胶质瘤细胞，如增加的荧光染料转移所示。
Enzyme prodrug therapy using neural progenitor cells (NPCs) as delivery vehicles has been applied in animal models of gliomas and relies on gap junction communication (GJC) between delivery and target cells. This study investigated the effects of histone deacetylase (HDAC) inhibitors on GJC for the purpose of facilitating transfer of therapeutic molecules from recombinant NPCs. We studied a novel immortalized midbrain cell line, NGC-407 of embryonic human origin having neural precursor characteristics, as a potential delivery vehicle. The expression of gap junction protein connexin 43 (C x 43) was analyzed by western blot and immunocytochemistry. While Cx43 levels were decreased in untreated differentiating NGC-407 cells, the HDAC inhibitor 4-phenylbutyrate (4-PB) increased C x 43 expression along with increased membranous deposition in both proliferating and differentiating cells. Simultaneously, Ser 279/282-phosphorylated form of Cx43 was declined in both culture conditions by 4-PB. The 4-PB effect in NGC-407 cells was verified by using HNSC 100 human neural progenitors and Trichostatin A. Improved functional GJC is of imperative importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds. We show here an enhancement by 4-PB, of the functional GJC among NGC-407 cells, as well as between NGC-407 and human glioma cells, as indicated by increased fluorescent dye transfer.