Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis

Chien Ju Lin, Ya An Chang, Yi Ling Lin, Shing Hwa Liu, Cheng Kuei Chang, Ruei Ming Chen

研究成果: 雜誌貢獻文章

24 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)517-527
頁數11
期刊Phytomedicine
23
發行號5
DOIs
出版狀態已發佈 - 五月 15 2016

指紋

G1 Phase
Glioblastoma
Apoptosis
Glioma
Cyclin D1
Cell Cycle Checkpoints
Nude Mice
honokiol
Phosphorylation
G1 Phase Cell Cycle Checkpoints
Activity Cycles
Caspase 9
Caspase 8
Polyphenols
Caspases
Blood-Brain Barrier
Neuroblastoma
Caspase 3
Cell Survival
Down-Regulation

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Pharmaceutical Science
  • Complementary and alternative medicine
  • Molecular Medicine

引用此文

Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis. / Lin, Chien Ju; Chang, Ya An; Lin, Yi Ling; Liu, Shing Hwa; Chang, Cheng Kuei; Chen, Ruei Ming.

於: Phytomedicine, 卷 23, 編號 5, 15.05.2016, p. 517-527.

研究成果: 雜誌貢獻文章

Lin, Chien Ju ; Chang, Ya An ; Lin, Yi Ling ; Liu, Shing Hwa ; Chang, Cheng Kuei ; Chen, Ruei Ming. / Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis. 於: Phytomedicine. 2016 ; 卷 23, 編號 5. 頁 517-527.
@article{46eb5335852a484eaa312528c80dd015,
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. 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.",
keywords = "Apoptosis, Cell cycle arrest, Honokiol, Malignant glioma, p53/CD1/CDKs/E2F1",
author = "Lin, {Chien Ju} and Chang, {Ya An} and Lin, {Yi Ling} and Liu, {Shing Hwa} and Chang, {Cheng Kuei} and Chen, {Ruei Ming}",
year = "2016",
month = "5",
day = "15",
doi = "10.1016/j.phymed.2016.02.021",
language = "English",
volume = "23",
pages = "517--527",
journal = "Phytomedicine",
issn = "0944-7113",
publisher = "Urban und Fischer Verlag Jena",
number = "5",

}

TY - JOUR

T1 - Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis

AU - Lin, Chien Ju

AU - Chang, Ya An

AU - Lin, Yi Ling

AU - Liu, Shing Hwa

AU - Chang, Cheng Kuei

AU - Chen, Ruei Ming

PY - 2016/5/15

Y1 - 2016/5/15

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cell cycle arrest

KW - Honokiol

KW - Malignant glioma

KW - p53/CD1/CDKs/E2F1

UR - http://www.scopus.com/inward/record.url?scp=84962224173&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962224173&partnerID=8YFLogxK

U2 - 10.1016/j.phymed.2016.02.021

DO - 10.1016/j.phymed.2016.02.021

M3 - Article

C2 - 27064011

AN - SCOPUS:84962224173

VL - 23

SP - 517

EP - 527

JO - Phytomedicine

JF - Phytomedicine

SN - 0944-7113

IS - 5

ER -