TY - JOUR
T1 - Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells
AU - Chio, Chung Ching
AU - Chen, Kung Yen
AU - Chang, Cheng Kuei
AU - Chuang, Jian Ying
AU - Liu, Chih Chung
AU - Liu, Shing Hwa
AU - Chen, Ruei Ming
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/4/3
Y1 - 2018/4/3
N2 - Background: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms. Methods: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. Results: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. Conclusions: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.
AB - Background: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms. Methods: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. Results: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. Conclusions: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.
KW - Autophagy and apoptosis
KW - Drug tolerance
KW - Glioma cells
KW - Honokiol
KW - Temozolomide
KW - Caspase 3/metabolism
KW - Humans
KW - Apoptosis/drug effects
KW - Autophagy/drug effects
KW - Lignans/pharmacology
KW - Drug Resistance, Neoplasm/drug effects
KW - Cell Survival/drug effects
KW - Biphenyl Compounds/pharmacology
KW - Drug Synergism
KW - Glioma
KW - Antineoplastic Agents, Phytogenic/pharmacology
KW - Cell Line, Tumor
KW - Cell Cycle Checkpoints/drug effects
KW - Temozolomide/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85044869266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044869266&partnerID=8YFLogxK
U2 - 10.1186/s12885-018-4267-z
DO - 10.1186/s12885-018-4267-z
M3 - Article
C2 - 29614990
AN - SCOPUS:85044869266
SN - 1471-2407
VL - 18
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 379
ER -