EDL-360: A Potential Novel Antiglioma Agent.
EDL-360: A Potential Novel Antiglioma Agent.
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DOI：
10.4172/1948-5956.1000295
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发表时间：
2014-09-25
期刊：
影响因子：
--
通讯作者：
Pfeffer LM
中科院分区：
文献类型：
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作者：
Hosni-Ahmed A;Sims M;Jones TS;Patil R;Patil S;Abdelsamed H;Yates CR;Miller DD;Pfeffer LM
神经胶质瘤是一种由神经胶质细胞或神经胶质祖细胞引起的脑肿瘤，占美国恶性脑肿瘤发病率的80%。多形性胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤恶性肿瘤，少于8%的GBM患者存活超过3年。在过去的10年里，尽管癌症的诊断和治疗有所改善，但高级别胶质瘤患者的生存率仍然令人沮丧。我们研究的主要焦点是鉴定有效的新型抗胶质瘤小分子。我们以前表明，EDL-360，四氢异喹啉（THIQ）类似物，作为高度细胞毒性的人类神经胶质瘤细胞培养。在这里，我们表明，EDL-360显着诱导人胶质瘤细胞系（U87和LN 18）的凋亡。然而，在正常星形胶质细胞中，EDL-360诱导了适度的G 0/G1细胞周期停滞，但不诱导凋亡。为了增强EDL-360诱导的细胞死亡，我们测试了用EDL-360和恩贝林（embelin）（抗凋亡蛋白XIAP的抑制剂）的同时处理。我们发现，与单独的EDL-360相比，当EDL-360和恩贝林组合使用时，胶质瘤细胞具有显著较低的存活率。我们还使用了EDL-360与癸基泛醌（dUb）（一种半胱天冬酶-9抑制剂）的组合处理，并且发现当与单独用EDL-360处理相比时，组合处理诱导显著的细胞死亡。这是第一个报告，表明dUb具有抗癌活性，并可能作为XIAP抑制剂。最后，我们的体内数据显示，如H&E染色所示，EDL-360处理诱导神经胶质瘤肿瘤发生的部分消退并诱导经处理的肿瘤中的细胞死亡。总之，这些数据表明，EDL-360具有治疗神经胶质瘤的潜在治疗应用，特别是当与XIAP抑制剂组合时。
Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL-360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL-360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, our in vivo data showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.