Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.
Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.
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DOI：
10.1371/journal.pone.0013879
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发表时间：
2010-11-08
期刊：
影响因子：
3.7
通讯作者：
Perez-Castillo A
中科院分区：
文献类型：
--
作者：
Aguilar-Morante D;Morales-Garcia JA;Sanz-SanCristobal M;Garcia-Cabezas MA;Santos A;Perez-Castillo A
噻二唑烷酮（TDZD）是一类非ATP竞争性糖原合成酶激酶3β（GSK-3β）抑制剂。在这项研究中，我们分析了4-苄基-2-甲基-1，2，4-噻二唑烷-3，5-二酮（TDZD-8）对小鼠GL 261细胞体外生长和对小鼠脑内胶质瘤体内生长的影响。我们的数据表明，TDZD-8在体外降低了GL 261胶质母细胞瘤细胞的增殖并诱导了细胞凋亡，在体内延迟了肿瘤生长，并提高了动物存活率。这些作用与细胞外信号调节激酶（ERK）通路的早期激活和EGR-1和p21基因表达增加有关。此外，我们观察到ERK通路的持续激活，伴随的核糖体S6激酶（p90 RSK）的磷酸化和激活以及GSK-3β通过Ser 9磷酸化的失活。最后，用TDZD-8处理胶质母细胞瘤干细胞导致这些细胞的增殖和自我更新受到抑制。我们的研究结果表明，TDZD-8使用一种新的机制来靶向胶质母细胞瘤细胞，并且恶性祖细胞群体可能是该化合物的靶点。
Thiadiazolidinones (TDZD) are small heterocyclic compounds first described as non-ATP competitive inhibitors of glycogen synthase kinase 3β (GSK-3β). In this study, we analyzed the effects of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), on murine GL261 cells growth in vitro and on the growth of established intracerebral murine gliomas in vivo. Our data show that TDZD-8 decreased proliferation and induced apoptosis of GL261 glioblastoma cells in vitro, delayed tumor growth in vivo, and augmented animal survival. These effects were associated with an early activation of extracellular signal-regulated kinase (ERK) pathway and increased expression of EGR-1 and p21 genes. Also, we observed a sustained activation of the ERK pathway, a concomitant phosphorylation and activation of ribosomal S6 kinase (p90RSK) and an inactivation of GSK-3β by phosphorylation at Ser 9. Finally, treatment of glioblastoma stem cells with TDZD-8 resulted in an inhibition of proliferation and self-renewal of these cells. Our results suggest that TDZD-8 uses a novel mechanism to target glioblastoma cells, and that malignant progenitor population could be a target of this compound.
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