Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model
Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model
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DOI：
10.1016/j.canlet.2018.11.027
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Shin, Hwa Kyoung
中科院分区：
文献类型：
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作者：
Hwang, Ji Young;Park, Jung Hwa;Shin, Hwa Kyoung
多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，仍然无法治愈。植物提取物是有效抗癌药物的潜在来源。在这项研究中，我们研究了异乌药内酯从乌药对肿瘤生长的影响，使用U-87人胶质母细胞瘤细胞。用异吲哚内酯处理抑制细胞活力并促进凋亡性细胞死亡。此外，腹膜内注射异茚内酯显著抑制人GBM异种移植小鼠模型中的肿瘤生长。为了确定参与诱导异松内酯处理的细胞凋亡的蛋白质，我们进行了人类凋亡蛋白质组阵列分析和蛋白质印迹。异茚内酯抑制B细胞淋巴瘤2（BCL-2）以及生存素和X连锁凋亡抑制蛋白（XIAP）（称为凋亡抑制剂）的表达，并增加裂解的caspase-3的水平。此外，异茚内酯处理增加裂解的聚（ADP-核糖）聚合酶（PARP）和DNA损伤。在异种移植瘤组织中，我们观察到高的免疫荧光裂解的caspase-3和TUNEL的异茚内酯治疗组。总之，异茚内酯在体外和体内增强U-87 GBM细胞凋亡并延缓肿瘤生长，表明异茚内酯可能是抗胶质母细胞瘤药物开发的潜在候选者。
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of iso-linderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.