Hosni-Ahmed Amira, Sims Michelle, Jones Terreia S, Patil Renukadevi, Patil Shivaputra, Abdelsamed Hossam, Yates Charles R, Miller Duane D, Pfeffer Lawrence M
Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, USA ; The Center for Cancer Research, University of Tennessee Health Science Center, USA ; Department of Chemistry, College of Science, Fayoum University, Fayoum, Egypt.
Departments of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, USA ; The Center for Cancer Research, University of Tennessee Health Science Center, USA.
J Cancer Sci Ther. 2014 Sep 25;6(9):370-377. doi: 10.4172/1948-5956.1000295.
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 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.
神经胶质瘤是一种起源于神经胶质细胞或神经胶质祖细胞的脑肿瘤，在美国占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，GBM患者存活超过3年的不到8%。在过去10年中，尽管癌症的诊断和治疗有所改善，但高级别神经胶质瘤患者的生存率仍然很低。我们研究的主要重点是鉴定有效的新型抗神经胶质瘤小分子。我们之前表明，四氢异喹啉（THIQ）类似物EDL-360对人神经胶质瘤细胞培养物具有高度细胞毒性。在此我们表明，EDL-360在人神经胶质瘤细胞系（U87和LN18）中显著诱导细胞凋亡。然而，在正常星形胶质细胞中，EDL-360诱导适度的G0/G1细胞周期停滞，但不诱导细胞凋亡。为了增强EDL-360诱导的细胞死亡，我们测试了EDL-360与 embelin（一种抗凋亡蛋白XIAP的抑制剂）同时治疗。我们发现，与单独使用EDL-360相比，联合使用EDL-360和embelin时神经胶质瘤细胞的活力显著降低。我们还使用了EDL-360与半胱天冬酶-9抑制剂癸基泛醌（dUb）的联合治疗，发现与单独使用EDL-360治疗相比，联合治疗诱导显著的细胞死亡。这是第一份表明dUb具有抗癌活性且可能作为XIAP抑制剂的报告。最后，我们的数据表明，EDL-360治疗在神经胶质瘤肿瘤发生中诱导部分消退，并如苏木精和伊红染色所示在治疗的肿瘤中诱导细胞死亡。综上所述，这些数据表明EDL-360在治疗神经胶质瘤方面具有潜在的治疗应用，特别是与XIAP抑制剂联合使用时。
