title: Honokiol traverses the blood-brain barrier and induces apoptosis of neuroblastoma cells via an intrinsic bax-mitochondrion-cytochrome c-caspase protease pathway.
abstract: Neuroblastomas, an embryonic cancer of the sympathetic nervous system, often occur in young children. Honokiol, a small-molecule polyphenol, has multiple therapeutic effects and pharmacological activities. This study was designed to evaluate whether honokiol could pass through the blood-brain barrier (BBB) and induce death of neuroblastoma cells and its possible mechanisms. Primary cerebral endothelial cells (CECs) prepared from mouse brain capillaries were cultured at a high density for 4 days, and these cells formed compact morphologies and expressed the ZO-1 tight-junction protein. A permeability assay showed that the CEC-constructed barrier obstructed the passing of FITC-dextran. Analyses by high-performance liquid chromatography and the UV spectrum revealed that honokiol could traverse the CEC-built junction barrier and the BBB of ICR mice. Exposure of neuroblastoma neuro-2a cells and NB41A3 cells to honokiolinduced cell shrinkage and decreased cell viability. In parallel, honokiol selectively induced DNA fragmentation and cell apoptosis rather than cell necrosis. Sequential treatment of neuro-2a cells with honokiol increased the expression of the proapoptotic Bax protein and its translocation from the cytoplasm to mitochondria. Honokiol successively decreased the mitochondrial membrane potential but increased the release of cytochrome c from mitochondria. Consequently, honokiol induced cascade activation of caspases-9, -3, and -6. In comparison, reducing caspase-6 activity by Z-VEID-FMK, an inhibitor of caspase-6, simultaneously attenuated honokiol-induced DNA fragmentation and cell apoptosis. Taken together, this study showed that honokiol can pass through the BBB and induce apoptotic insults to neuroblastoma cells through a Bax-mitochondrion-cytochrome c-caspase protease pathway. Therefore, honokiol may be a potential candidate drug for treating brain tumors.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing St, Taipei 110, Taiwan.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Lin
authors.forename: Juei-Tai
authors.initials: JT
authors.lastname: Chen
authors.forename: Chung-Ye
authors.initials: CY
authors.lastname: Hong
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Wang
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Yao
authors.forename: Gi-Ming
authors.initials: GM
authors.lastname: Lai
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D020169:Caspases; D045304:Cytochromes c; D017705:Lignans; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols