title: Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis.
abstract: BACKGROUND
  Our previous study showed that honokiol, a bioactive polyphenol, can traverse the blood-brain barrier and kills neuroblastoma cells.
  
  
  OBJECTIVE
  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.
authors.affiliation: Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chien-Ju
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ya-An
authors.initials: YA
authors.lastname: Chang
authors.affiliation: Brain Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University Wan-Fang Hospital, Taipei, Taiwan.
authors.forename: Cheng-Kuei
authors.initials: CK
authors.lastname: Chang
authors.affiliation: Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Brain Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan; Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: rmchen@tmu.edu.tw.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D052160:Benzothiazoles; D001713:Biphenyl Compounds; D020169:Caspases; D018797:Cell Cycle Proteins; D017705:Lignans; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C121565:pifithrin
keywords: Apoptosis; Cell cycle arrest; Honokiol; Malignant glioma; p53/CD1/CDKs/E2F1