Inhibition of Phosphatidylinositol 3-Kinase/AKT Signaling by NVP-BKM120 Promotes ABT-737-Induced Toxicity in a Caspase-Dependent Manner through Mitochondrial Dysfunction and DNA Damage Response in Established and Primary Cultured Glioblastoma Cells
Inhibition of Phosphatidylinositol 3-Kinase/AKT Signaling by NVP-BKM120 Promotes ABT-737-Induced Toxicity in a Caspase-Dependent Manner through Mitochondrial Dysfunction and DNA Damage Response in Established and Primary Cultured Glioblastoma Cells
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DOI：
10.1124/jpet.114.212910
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Pollack, Ian F.
中科院分区：
文献类型：
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作者：
Jane, Esther P.;Premkumar, Daniel R.;Pollack, Ian F.
在包括神经胶质瘤在内的许多癌症中，对可能增强B细胞淋巴瘤-2（Bcl-2）抑制剂ABT-737 [N-{4-[4（4-氯-联苯-2-基甲基）-哌嗪-1-基]-苯甲酰基}-4（3-二甲氨基-1-苯硫基甲基-丙氨基）-3硝基-苯磺酰胺]的功效的治疗策略的鉴定是非常感兴趣的。我们最近的研究表明，Akt是胶质瘤细胞系对ABT 737的凋亡敏感性的关键介质。磷脂酰肌醇3-激酶（PI 3 K）/ Akt抑制剂目前正在胶质瘤患者中进行临床评估。由于PI 3 K/ Akt抑制预期具有许多促凋亡作用，我们假设PI 3 K抑制剂和Bcl-2同源3模拟物之间可能存在独特的协同作用。为此，我们评估了PI 3 K/ Akt抑制剂NVP-BKM 120 [5-（2，6-二吗啉代嘧啶-4基）-4-（三氟甲基）吡啶-2-胺]和Bcl-2家族抑制剂ABT-737在建立的和原代培养的神经胶质瘤细胞中的组合。我们发现，这些药物的联合治疗导致了caspase-8和-3，PARP的显著激活和细胞死亡，而与PTEN状态无关。用该组合观察到的增强的致死性似乎也依赖于线粒体膜电位的损失和细胞色素c、smac/ DIABLO和凋亡诱导因子向胞质溶胶的释放。进一步研究发现，这些抑制剂引起的Noxa上调、Bid截短、Bax和巴克活化是协同作用的关键因素。此外，我们证明了促凋亡蛋白Bim和巴克从Mcl-1的释放。我们发现染色体分离缺陷导致多核细胞和集落形成能力丧失，这表明NVP-BKM 120可能用作提高ABT-737抗癌活性的有前途的药物。
Identification of therapeutic strategies that might enhance the efficacy of B-cell lymphoma-2 (Bcl-2) inhibitor ABT-737 [N-{4-[4( 4-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4( 3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3nitro- benzenesulfonamide] is of great interest in many cancers, including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT737 in glioma cell lines. Inhibitors of phosphatidylinositol 3-kinase (PI3K)/ Akt are currently being assessed clinically in patients with glioma. Because PI3K/ Akt inhibition would be expected to have many proapoptotic effects, we hypothesized that there may be unique synergy between PI3K inhibitors and Bcl-2 homology 3 mimetics. Toward this end, we assessed the combination of the PI3K/ Akt inhibitor NVP-BKM120 [5-(2,6-dimorpholinopyrimidin-4yl)- 4-(trifluoromethyl) pyridin-2-amine] and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8 and -3, PARP, and cell death, irrespective of PTEN status. The enhanced lethality observed with this combination also appears dependent on the loss of mitochondrial membrane potential and release of cytochrome c, smac/ DIABLO, and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, and activation of Bax and Bak caused by these inhibitors were the key factors for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony-forming ability, suggesting the potential use of NVP-BKM120 as a promising agent to improve the anticancer activities of ABT-737.