Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis
Journal
Phytomedicine
Journal Volume
23
Journal Issue
5
Pages
517-527
Date Issued
2016
Author(s)
Abstract
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-α (PFN-α), 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-α 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-α. 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. ? 2016 Elsevier GmbH. All rights reserved.
Subjects
Apoptosis; Cell cycle arrest; Honokiol; Malignant glioma; p53/CD1/CDKs/E2F1
SDGs
Other Subjects
beta actin; caspase 3; caspase 8; caspase 9; cyclin D1; cyclin dependent kinase 4; cyclin dependent kinase 6; honokiol; pifithrin alpha; protein p21; protein p53; transcription factor E2F1; benzothiazole derivative; biphenyl derivative; caspase; cell cycle protein; honokiol; lignan; pifithrin; protein p53; toluene; TP53 protein, human; animal cell; animal experiment; animal model; animal tissue; apoptosis; Article; cancer cell line; cell cycle arrest; cell viability; controlled study; down regulation; drug mechanism; female; G1 phase cell cycle checkpoint; glioblastoma; glioma cell; human; human cell; IC50; immunohistochemistry; in vitro study; mouse; nonhuman; priority journal; protein phosphorylation; signal transduction; analogs and derivatives; animal; apoptosis; Bagg albino mouse; cell cycle checkpoint; cell cycle G1 phase; drug effects; glioblastoma; metabolism; nude mouse; preclinical study; tumor cell line; Animals; Apoptosis; Benzothiazoles; Biphenyl Compounds; Caspases; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Down-Regulation; Drug Evaluation, Preclinical; Female; G1 Phase; Glioblastoma; Humans; Lignans; Mice; Mice, Inbred BALB C; Mice, Nude; Toluene; Tumor Suppressor Protein p53
Type
journal article