Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis
Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis
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DOI：
10.1016/j.phymed.2016.02.021
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发表时间：
2016-05-15
期刊：
影响因子：
7.9
通讯作者：
Chen, Ruei-Ming
中科院分区：
文献类型：
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作者：
Lin, Chien-Ju;Chang, Ya-An;Chen, Ruei-Ming
背景资料：目的：探讨和厚朴酚对恶性胶质瘤的作用及其可能的机制，方法：观察和厚朴酚对人胶质瘤细胞株U87 MG和U373 MG的活性、caspase活性、细胞凋亡和细胞周期阻滞的影响。免疫组化检测p53、p21、CDK 6、CDK 4、cyclin D1和E2 F1的失活或磷酸化水平。将p53抑制剂Pifithrin-alpha（PFN-alpha）预处理到细胞中。最后，我们在体外的研究结果证实了使用颅内移植U87 MG cells.Results的人U87 MG胶质瘤细胞暴露于honoklavine降低细胞活力。与此同时，和厚朴诱导caspase-8，-9和-3，细胞凋亡和G1期细胞周期阻滞的激活。用和诺啡肽处理U87 MG细胞可增加p53磷酸化和p21水平。和厚朴引起CDK 6、CDK 4、细胞周期蛋白D1、磷酸化（p）RB和E2 F1的信号转导下调。用PFN-alpha预处理U87 MG细胞显著逆转和厚朴酚诱导的p53磷酸化和p21扩增。PFN-α可减弱和厚朴酚诱导的CDK 6、CDK 4、细胞周期蛋白D1、p-RB和E2 F1水平的改变。此外，和厚朴酚还能诱导U373 MG胶质瘤细胞凋亡。在我们的体内模型中，施用和厚朴酚延长了植入U87 MG细胞的裸鼠的存活率，并诱导caspase-3活化和p53、p21、CDK 6、CDK 4、cyclin D1、p-RB和E2 F1的时间变化。和诺平可通过激活p53/cyclin D1/CDK 6/CDK 4/E2 F1 - 1/E2 F1/E2依赖路径我们的研究结果表明，和厚朴酚治疗人类恶性胶质瘤的潜力。(C)2016 Elsevier GmbH. All rights reserved.
Background: Our previous study showed that honokiol, a bioactive polyphenol, can traverse the blood-brain barrier and kills neuroblastoma cells.Purpose: In this study, we further evaluated the preclinical effects of honokiol on development of malignant glioma and the possible mechanisms.Methods: Effects of honokiol on viability, caspase activities, apoptosis, and cell cycle arrest in human glioma U87 MG or U373MG cells were assayed. As to the mechanisms, levels of inactive or phosphorylated (p) p53, p21, CDK6, CDK4, cyclin D1, and E2F1 were immunodetected. Pifithrin-alpha (PFN-alpha), a p53 inhibitor, was pretreated into the cells. Finally, our in vitro findings were confirmed using intracranial nude mice implanted with U87 MG cells.Results: Exposure of human U87 MG glioma cells to honokiol decreased the cell viability. In parallel, honokiol induced activations of caspase-8, -9, and -3, apoptosis, and G1 cell cycle arrest. Treatment of U87 MG cells with honokiol increased p53 phosphorylation and p21 levels. Honokiol provoked signal-transducing downregulation of CDK6, CDK4, cyclin D1, phosphorylated (p)RB, and E2F1. Pretreatment of U87 MG cells with PFN-alpha significantly reversed honokiol-induced p53 phosphorylation and p21 augmentation. Honokiol-induced alterations in levels of CDK6, CDK4, cyclin D1, p-RB, and E2F1 were attenuated by PFN-alpha. Furthermore, honokiol could induce apoptotic insults to human U373MG glioma cells. In our in vivo model, administration of honokiol prolonged the survival rate of nude mice implanted with U87 MG cells and induced caspase-3 activation and chronological changes in p53, p21, CDK6, CDK4, cyclin D1, p-RB, and E2F1.Conclusions: Honokiol can repress human glioma growth by inducing apoptosis and cell cycle arrest in tumor cells though activating a p53/cyclin D1/CDK6/CDK4/E2F1-dependent pathway. Our results suggest the potential of honokiol in therapies for human malignant gliomas. (C) 2016 Elsevier GmbH. All rights reserved.