title: The mechanism of honokiol-induced intracellular Ca(2+) rises and apoptosis in human glioblastoma cells.
abstract: Honokiol, an active constituent of oriental medicinal herb Magnolia officinalis, caused Ca(2+) mobilization and apoptosis in different cancer cells. In vivo, honokiol crossed the blood-brain or -cerebrospinal fluid barrier, suggesting that it may be an effective drug for the treatment of brain tumors, including glioblastoma. This study examined the effect of honokiol on intracellular Ca(2+) concentration ([Ca(2+)]i) and apoptosis in DBTRG-05MG human glioblastoma cells. Honokiol concentration-dependently induced a [Ca(2+)]i rise. The signal was decreased partially by removal of extracellular Ca(2+). Honokiol-triggered [Ca(2+)]i rise was not suppressed by store-operated Ca(2+) channel blockers (nifedipine, econazole, SK&F96365) and the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate (PMA), but was inhibited by the PKC inhibitor GF109203X. GF109203X-induced inhibition was not altered by removal of extracellular Ca(2+). In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) abolished honokiol-induced [Ca(2+)]i rise. Conversely, incubation with honokiol abolished TG or BHQ-induced [Ca(2+)]i rise. Inhibition of phospholipase C (PLC) with U73122 abolished honokiol-induced [Ca(2+)]i rise. Honokiol (20-80μM) reduced the cell viability, which was not reversed by prechelating cytosolic Ca(2+) with BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester). Honokiol (20-60μM) enhanced reactive oxygen species (ROS) production, decreased mitochondrial membrane potential, released cytochrome c, and activated caspase-9/caspase-3. Together, honokiol induced a [Ca(2+)]i rise by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-dependent, non store-operated Ca(2+) channels. Moreover, honokiol activated the mitochondrial pathway of apoptosis in DBTRG-05MG human glioblastoma cells.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan, ROC.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.affiliation: Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC.
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Gastroenterology, Kaohsiung Veterans General Hospital-Pingtung Branch 912, Taiwan, ROC.
authors.forename: Kuang-Chung
authors.initials: KC
authors.lastname: Ko
authors.affiliation: Department of Pharmacy, Kaohsiung Veterans General Hospital-Pingtung Branch 912, Taiwan, ROC.
authors.forename: Ni-Na
authors.initials: NN
authors.lastname: Chiang
authors.affiliation: Department of Pharmacy, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung 802, Taiwan, ROC.
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, ROC. Electronic address: pseudoo67@gmail.com.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology; D005909:Glioblastoma / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D002118:Calcium; D004963:Estrenes; D017705:Lignans; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Apoptosis; Ca(2+); Honokiol; Human glioblastoma cells; Mitochondrial membrane potential