α-Carboline derivative TJY-16 inhibits tumor growth by inducing G2/M cell cycle arrest in glioma cells
α-Carboline derivative TJY-16 inhibits tumor growth by inducing G2/M cell cycle arrest in glioma cells
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DOI：
10.1186/s12929-016-0222-y
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发表时间：
2016-01-19
影响因子：
11
通讯作者：
Gean, Po-Wu
中科院分区：
文献类型：
--
作者：
Huang, Hsiao-Chieh;Liu, Wei-Ting;Gean, Po-Wu
背景资料：多形性胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤，尽管手术、放疗和化疗取得了进展，但仍然难以治愈。因此，新药的开发是迫切需要的。α-咔啉衍生物通常分离自海洋动物，如不列颠海洋被囊动物Dendrodoa grossularia和印度尼西亚海鞘Polycarpa aurata。在本研究中，我们合成了几种α-咔啉类化合物，并检测了它们的抗胶质瘤活性。结果：我们报道，在α-咔啉类化合物中，TJY-16（6-乙酰基-9-（3，4，5-三甲氧基苄基）-9H-吡啶并[2，3-B]吲哚）是诱导胶质瘤细胞死亡的最有效的α-咔啉类似物，IC 50值约为50 nM。TJY-16以浓度和时间依赖性方式降低胶质瘤细胞的细胞活力。台盼蓝拒染法显示细胞活力的降低是由于细胞生长抑制和细胞死亡。流式细胞仪分析显示TJY-16可诱导细胞G2/M期阻滞，随后诱导亚G1期。Hoechst染色可见细胞核皱缩、DNA浓缩等凋亡特征。Western blot分析显示，切割的caspase-3水平增加。caspase-8的激活和线粒体膜电位的去极化（.. m）表明TJY-16诱导的细胞凋亡既有内源性途径也有外源性途径参与。TJY-16能有效抑制U87胶质瘤细胞移植瘤的生长，并能诱导caspase-3的活化。结论：TJY-16可能通过诱导G2/M期细胞阻滞，进而诱导细胞凋亡来杀伤胶质瘤细胞。因此，TJY-16是治疗恶性胶质瘤的一种有前途的药物。
Background: Glioblastoma multiforme (GBM) is the most lethal primary brain tumors which remains difficult to cure despite advances in surgery, radiotherapy and chemotherapy. Therefore, the development of new drug is urgently needed. a-carboline derivatives were usually isolated from marine animals such as Britannia marine tunicate Dendrodoa grossularia and Indonesian ascidian Polycarpa aurata. In this study, we have synthesized several a-carboline compounds and examined their anti-glioma activities.Results: We report that among a-carboline derivatives TJY-16 (6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b] indole) is the most potent a-carboline analog to induce glioma cell death with IC50 value of around 50 nM. TJY-16 decreased cell viability of glioma cells in a concentration-and time-dependent manner. Trypan blue exclusion assay showed that the reduction of cell viability was due to both cell growth inhibition and cell death. Flow cytometric analysis showed that TJY-16 induced G2/M cell cycle arrest followed by induction of sub-G1 phase. Hoechst staining detected the apoptotic features such as nuclear shrinkage and DNA condensation. Western blot analysis showed the increased level of cleaved caspase-3. The activation of caspase-8 and depolarization of mitochondrial membrane potential (..m) indicated that both extrinsic and intrinsic apoptotic pathways were involved in TJY-16-induced apoptosis. TJY-16 effectively inhibited tumor growth and induced caspase-3 activation in the xenograft tumor model of U87 glioma cells.Conclusions: Our results suggest that TJY-16 may kill glioma cells by inducing G2/M cell cycle arrest followed by apoptosis. Thus, TJY-16 is a promising agent for the treatment of malignant gliomas.