Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells.
Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells.
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DOI：
10.1158/1078-0432.ccr-11-1558
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Yung WK
中科院分区：
文献类型：
--
作者：
Koul D;Fu J;Shen R;LaFortune TA;Wang S;Tiao N;Kim YW;Liu JL;Ramnarian D;Yuan Y;Garcia-Echevrria C;Maira SM;Yung WK
本研究的目的是在体外和体内展示NVP-BKM120在人胶质母细胞瘤（GBM）细胞中的临床前疗效和临床开发潜力，NVP-BKM120是一种选择性的pan类磷脂酰肌醇-3激酶（PI3K）抑制剂。采用细胞滴度-蓝法评价NVP-BKM120对细胞生长的影响。流式细胞术检测细胞周期、凋亡和有丝分裂指数。免疫荧光法检测有丝分裂突变。采用颅内U87胶质瘤模型检测NVP-BKM120的疗效。我们在一组胶质瘤细胞系中测试了选择性PI3K抑制剂NVP-BKM120的生物学效应。NVP-BKM120治疗72小时可产生剂量依赖性生长抑制，并有效阻断PI3K/Akt信号级联。虽然我们发现细胞系对NVP-BKM120的敏感性与磷酸酶和紧张素同源物（PTEN）和表皮生长因子受体（EGFR）状态之间没有明显的关系，但我们确实观察到p53状态的不同敏感性模式，胶质瘤细胞含有野生型p53比p53突变或缺失的细胞更敏感。NVP-BKM120在细胞p53状态的基础上显示出不同形式的细胞死亡，p53野生型细胞发生凋亡细胞死亡，p53突变/缺失细胞发生有丝分裂突变细胞死亡。NVP-BKM120主要通过Aurora B激酶介导有丝分裂突变。p53野生型U87胶质瘤细胞中p53的敲低表现为微管错位、多个中心体和有丝分裂突变细胞死亡。在体外评估该化合物的同时，使用颅内U87肿瘤模型进行的体内疗效研究显示，中位生存期从26天（对照组）增加到38天和48天（治疗组）。我们目前的研究结果表明，NVP-BKM120抑制PI3K信号通路，导致基于p53状态的不同形式的细胞死亡。需要进一步的研究来确定NVP-BKM120是否具有治疗胶质瘤的潜力。
The aim of this study was to show preclinical efficacy and clinical development potential of NVP-BKM120, a selective pan class I phosphatidylinositol-3 kinase (PI3K) inhibitor in human glioblastoma (GBM) cells in vitro and in vivo. The effect of NVP-BKM120 on cellular growth was assessed by CellTiter-Blue assay. Flow cytometric analyses were carried out to measure the cell-cycle, apoptosis, and mitotic index. Mitotic catastrophe was detected by immunofluorescence. The efficacy of NVP-BKM120 was tested using intracranial U87 glioma model. We tested the biologic effects of a selective PI3K inhibitor NVP-BKM120 in a set of glioma cell lines. NVP-BKM120 treatment for 72 hours resulted in a dose-dependent growth inhibition and effectively blocked the PI3K/Akt signaling cascade. Although we found no obvious relationship between the cell line's sensitivity to NVP-BKM120 and the phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) statuses, we did observe a differential sensitivity pattern with respect to p53 status, with glioma cells containing wild-type p53 more sensitive than cells with mutated or deleted p53. NVP-BKM120 showed differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death. NVP-BKM120 mediates mitotic catastrophe mainly through Aurora B kinase. Knockdown of p53 in p53 wild-type U87 glioma cells displayed microtubule misalignment, multiple centrosomes, and mitotic catastrophe cell death. Parallel to the assessment of the compound in in vitro settings, in vivo efficacy studies using an intracranial U87 tumor model showed an increased median survival from 26 days (control cohort) to 38 and 48 days (treated cohorts). Our present findings establish that NVP-BKM120 inhibits the PI3K signaling pathways, leading to different forms of cell death on the basis of p53 statuses. Further studies are warranted to determine if NVP-BKM120 has potential as a glioma treatment.