Casticin inhibits nasopharyngeal carcinoma growth by targeting phosphoinositide 3-kinase
Casticin inhibits nasopharyngeal carcinoma growth by targeting phosphoinositide 3-kinase
复制标题
Casticin 通过靶向磷酸肌醇 3-激酶抑制鼻咽癌生长
DOI：
10.1186/s12935-019-1069-6
复制
发表时间：
2019-12-21
影响因子：
5.8
通讯作者：
Yao, Kaitai
中科院分区：
文献类型：
--
作者：
Liu, Jingxian;Yang, Jinghong;Yao, Kaitai
研究背景牡荆素是从蔓荆子中提取的一种有效成分，具有抗炎、抗癌等多种药理活性。本研究的目的是探讨紫花苜蓿素在鼻咽癌细胞中的作用和机制，并确定其作为药物靶向应用的潜力。CCK-8测定和集落形成测定用于评估细胞活力。流式细胞仪检测细胞周期和凋亡（Annexin V/PI法）。一个三维（3D）肿瘤球培养系统被用来表征紫花苜蓿对NPC干细胞的影响。采用计算机分子对接预测和高通量KINOME扫描分析方法研究了紫花苜蓿素与磷脂酰肌醇3-激酶（PI 3 K）的结合，包括野生型和大多数突变体。我们还使用SelectScreen测定来检测靶激酶活性位点中ATP活性的IC 50。Western印迹法用于评估涉及细胞周期、凋亡、干性和PI 3 K/蛋白激酶B（AKT）信号传导的关键蛋白的变化。通过使用异种移植小鼠model.ResultsOur结果表明，紫花苜蓿素治疗在体内的效果进行了测定，是一种新的和新颖的选择性PI 3 K抑制剂，可以显着抑制NPC增殖，它诱导G2/GM逮捕和凋亡上调Bax/BCL 2的表达。此外，紫花苜蓿素被观察到影响的自我更新能力的鼻咽癌细胞株，并与BYL 719的组合，观察到诱导的磷酸化水平下降的mTORC 1下游靶点在BYL 719-不敏感的鼻咽癌细胞株。结论紫花苜蓿素是一种新出现的选择性PI 3 K抑制剂，有潜力作为一个针对性的治疗鼻咽癌。因此，紫花牡荆素可能代表一种新型且有效的抗NPC药物，并且可能具有与靶向PI 3 K/AKT的药理学药物联合使用的高潜力。
BackgroundCasticin, an isoflavone compound extracted from the herb Fructus Viticis, has demonstrated anti-inflammatory and anticancer activities and properties. The aim of this study was to investigate the effects and mechanisms of casticin in nasopharyngeal carcinoma (NPC) cells and to determine its potential for targeted use as a medicine.MethodsNPC cells were used to perform the experiments. The CCK‑8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell cycle and apoptosis analysis (annexin V/PI assay). A three-dimensional (3D) tumour sphere culture system was used to characterize the effect of casticin on NPC stem cells. In silico molecular docking prediction and high-throughput KINOME scan assays were used to evaluate the binding of casticin to phosphoinositide 3-kinase (PI3K), including wild-type and most of mutants variants. We also used the SelectScreen assay to detect the IC50 of ATP activity in the active site of the target kinase. Western blotting was used to evaluate the changes in key proteins involved cell cycle, apoptosis, stemness, and PI3K/protein kinase B (AKT) signalling. The effect of casticin treatment in vivo was determined by using a xenograft mouse model.ResultsOur results indicate that casticin is a new and novel selective PI3K inhibitor that can significantly inhibit NPC proliferation and that it induces G2/GM arrest and apoptosis by upregulating Bax/BCL2 expression. Moreover, casticin was observed to affect the self-renewal ability of the nasopharyngeal carcinoma cell lines, and a combination of casticin with BYL719 was observed to induce a decrease in the level of the phosphorylation of mTORC1 downstream targets in BYL719-insensitive NPC cell lines.ConclusionCasticin is a newly emerging selective PI3K inhibitor with potential for use as a targeted therapeutic treatment for nasopharyngeal carcinoma. Accordingly, casticin might represent a novel and effective agent against NPC and likely has high potential for combined use with pharmacological agents targeting PI3K/AKT.