Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red sobre Enfermedades neurodegenerativas, Madrid, Spain.
PLoS One. 2010 Nov 8;5(11):e13879. doi: 10.1371/journal.pone.0013879.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
噻二唑烷酮（TDZD）是首次被描述为非 ATP 竞争性糖原合酶激酶 3β（GSK-3β）抑制剂的小杂环化合物。在本研究中，我们分析了 4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）对体外培养的鼠 GL261 细胞生长以及体内已建立的脑内鼠神经胶质瘤生长的影响。
方法/主要发现：我们的数据表明，TDZD-8 可降低 GL261 神经胶质瘤细胞的体外增殖并诱导其凋亡，延迟体内肿瘤生长，并提高动物存活率。这些作用与细胞外信号调节激酶（ERK）途径的早期激活以及 EGR-1 和 p21 基因的表达增加有关。此外，我们观察到 ERK 途径的持续激活，核糖体 S6 激酶（p90RSK）的磷酸化和激活以及 GSK-3β 的磷酸化失活（Ser 9）。最后，用 TDZD-8 处理神经胶质瘤干细胞可抑制这些细胞的增殖和自我更新。
结论/意义：我们的结果表明，TDZD-8 利用一种新的机制来靶向神经胶质瘤细胞，而恶性祖细胞群体可能是该化合物的作用靶点。
