Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia
Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia
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DOI：
10.1007/s10637-011-9700-y
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发表时间：
2012-08-01
影响因子：
3.4
通讯作者：
Ong, Christopher J.
中科院分区：
文献类型：
--
作者：
Habibi, Darya;Ogloff, Nadya;Ong, Christopher J.
由于急性淋巴细胞白血病（ALL）成人患者的预后不良和治疗选择有限，因此迫切需要开发新的治疗方法来延长患者的生存期并提高其治疗效果。恶性T细胞需要高水平的营养物质来维持其增殖速度。疏螺旋体素是一种小分子的含腈大环内酯，是细菌和真核生物苏氨酰-tRNA合成酶的抑制剂。疏螺旋体素介导的氨酰-tRNA合成的抑制导致不带电荷的tRNA水平的诱导、营养应激和最终蛋白质合成的抑制。本研究的目的是调查疏螺旋体素治疗是否抑制恶性ALL细胞系，Jurkat和CEM细胞的增殖，并研究这种药物的作用机制。我们的研究结果表明，疏螺旋体素能够有效地抑制ALL细胞系的增殖，半最大抑制浓度为50 ng/ml。与原代成纤维细胞相比，疏螺旋体素对ALL细胞系显示出更大的抑制作用。流式细胞术和蛋白质印迹分析表明，疏螺旋体素能够增加ALL细胞系的凋亡水平，并导致G（1）阻滞。在用疏螺旋体素处理的ALL细胞系中，一般控制非去阻遏蛋白-2（GCN 2）激酶应激反应途径的激活和CHOP蛋白的诱导显著更高。这些发现共同表明，疏螺旋体素通过诱导细胞凋亡和介导G（1）阻滞靶向ALL细胞系，并且疏螺旋体素治疗ALL细胞系与GCN 2激酶途径的激活相关。
Due to the poor prognosis and limited therapeutic options for adult patients with acute lymphoblastic leukemia (ALL), development of novel therapies is much needed to prolong patient survival and increase the efficacy of their treatment. Malignant T cells need high levels of nutrients to maintain their proliferation rate. Borrelidin, a small molecule nitrile-containing macrolide, is an inhibitor of bacterial and eukaryal threonyl-tRNA synthetase. Borrelidin-mediated inhibition of aminoacyl-tRNA synthesis, leads to an induction in the levels of uncharged tRNA, nutritional stress and ultimately inhibition of protein synthesis. The aim of the present study was to investigate whether borrelidin treatment inhibits the proliferation of malignant ALL cell lines, Jurkat and CEM cells, and study the mechanism by which this drug acts. Our results show that borrelidin was able to potently inhibit the proliferation of ALL cell lines with a half maximal inhibitory concentration of 50 ng/ml. Borrelidin showed a greater inhibitory effect on ALL cell lines compared to primary fibroblasts. Flow cytometry and western blot analysis indicated that borrelidin was able to increase the level of apoptosis and cause G(1) arrest in ALL cell lines. Activation of the general control nonderepressible-2 (GCN2) kinase stress responsive pathway and induction of CHOP protein was significantly higher in ALL cell lines treated with borrelidin. These findings collectively suggest for the first time that borrelidin targets ALL cell lines by inducing apoptosis and mediating G(1) arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway.