Powerful tumor cell growth-inhibiting activity of a synthetic derivative of atractyligenin: Involvement of PI3K/Akt pathway and thioredoxin system
Powerful tumor cell growth-inhibiting activity of a synthetic derivative of atractyligenin: Involvement of PI3K/Akt pathway and thioredoxin system
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DOI：
10.1016/j.bbagen.2013.11.023
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发表时间：
2014-03-01
影响因子：
3
通讯作者：
Belisario, Maria Antonietta
中科院分区：
文献类型：
--
作者：
Cotugno, Roberta;Gallotta, Dario;Belisario, Maria Antonietta
背景：已有报道半合成的15-酮基苍术素甲基酯(SC2017)对多种实体瘤细胞株具有较高的抗增殖活性。本研究旨在研究SC2017在Jurkat细胞(T细胞白血病)和异种移植瘤模型中的生长抑制活性及其机制。用流式细胞仪监测细胞周期进程、活性氧(ROS)升高和细胞凋亡标志。用生化方法抑制硫氧还蛋白还原酶(TrxR)。免疫印迹法检测细胞内信号蛋白的水平和/或激活状态。结果：SC2017对Jurkat细胞具有生长抑制活性(半数抑制浓度IC50)，但对人外周血单个核细胞(PBMC)杀伤力较低。Jurkat细胞对SC2017的主要反应是G(2)期停滞，其次是caspase依赖的细胞凋亡。生化和药理学方法证实SC2017对PI3K/Akt通路和TrxR活性有抑制作用。结论：在体外和体内模型中，SC2017均能抑制肿瘤细胞的生长，但对PBMC表现出中等毒性。我们还证明了SC2017通过影响Akt的激活状态和TrxR功能来促进caspase依赖的Jurkat细胞的凋亡。一般意义：我们的观察表明半合成的Enkaurane SC2017是一种有前途的化疗化合物。事实上，SC2017已被证明具有肿瘤生长抑制活性，并能够中和PI3K/Akt和Tot系统生存信号。(C)2013爱思唯尔B.V.保留所有权利。
Background: The semi-synthetic ent-kaurane 15-ketoatractyligenin methyl ester (SC2017) has been previously reported to possess high antiproliferative activity against several solid tumor-derived cell lines. Our study was aimed at investigating SC2017 tumor growth-inhibiting activity and the underlying mechanisms in Jurkat cells (T-cell leukemia) and xenograft tumor models.Methods: Cell viability was evaluated by MU assay. Cell cycle progression, reactive oxygen species (ROS) elevation and apoptotic hallmarks were monitored by flow cytometry. Inhibition of thioredoxin reductase (TrxR) by biochemical assays. Levels and/or activation status of signaling proteins were assessed by western blotting. Xenograft tumors were generated with HCT 116 colon carcinoma cells.Results: SC2017 displayed cell growth-inhibiting activity against Jurkat cells (half maximal inhibitory concentration values (IC50) < 2 mu M), but low cell-killing potential in human peripheral blood mononuclear cells (PBMC). The primary response of Jurkat cells to SC2017 was an arrest in G(2) phase followed by caspase-dependent apoptosis. Inhibition of PI3K/Akt pathway and TrxR activity by SC2017 was demonstrated by biochemical and pharmacological approaches. At least, SC2017 was found to inhibit xenograft tumor growth.Conclusions: Our results demonstrate that SC2017 inhibits tumor cell growth in in vitro and in vivo models, but displays moderate toxicity against PBMC. We also demonstrate that SC2017 promotes caspase-dependent apoptosis in Jurkat cells by affecting Akt activation status and TrxR functionality.General significance: Our observations suggest the semi-synthetic ent-kaurane SC2017 as a promising chemotherapeutic compound. SC2017 has, indeed, shown to possess tumor growth inhibiting activity and be able to counteract PI3K/Akt and Tot system survival signaling. (C) 2013 Elsevier B.V. All rights reserved.