title: A novel berbamine derivative inhibits cell viability and induces apoptosis in cancer stem-like cells of human glioblastoma, via up-regulation of miRNA-4284 and JNK/AP-1 signaling.
abstract: Glioblastoma (GBM) is the most common primary brain tumor, accounting for approximately 40% of all central nervous system malignancies. Despite standard treatment consisting of surgical resection, radiotherapy and/or chemotherapy, the prognosis for GBM is poor; with a median survival of 14.6 months. The cancer stem cell or cancer-initiating cell model has provided a new paradigm for understanding development and recurrence of GBM following treatment. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plant, and along with its derivatives, has been shown to exhibit antitumor activity in several cancers. Here, we reported that a novel synthetic Berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of cancer stem-like cells (CSCs) in a time- and dose-dependent manner when the CSCs from four GBM patients (PBT003, PBT008, PBT022, and PBT030) were cultured. These CSCs grew in neurospheres and expressed CD133 and nestin as markers. Treatment with BBMD3 destroyed the neurosphere morphology, and led to the induction of apoptosis in the CSCs. Induction of apoptosis in these CSCs is dependent upon activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). MicroRNA-4284 (miR-4284) was shown to be over-expressed about 4-fold in the CSCs following BBMD3 treatment. Furthermore, transfection of synthetic anti-sense oligonucleotide against human miR-4284 partially blocked the anticancer effects of BBMD3 on the GBM derived CSCs. BBMD3 also increased phosphorylation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in an increase expression of phosphorylated c-Jun and total c-Fos; the major components of transcriptional factor AP-1. The JNK-c-Jun/AP-1 signaling pathway plays an important role in the induction of apoptosis in response to UV irradiation and some drug treatments. Targeting glioblastoma stem-like cells with BBMD3 is therefore novel, and may have promise as an effective therapeutic strategy for treating GBM patients.
authors.affiliation: Translational Biomarker Discovery Core, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.affiliation: Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Renate
authors.initials: R
authors.lastname: Starr
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Ma
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Horne
authors.affiliation: Molecular and Cellular Biology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Malkas
authors.affiliation: Vaccine & Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.affiliation: Translational Biomarker Discovery Core, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America; Molecular Pharmacology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hickey
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D044182:Benzylisoquinolines; C531388:MIRN27 microRNA, human; C000594473:MIRN4284 microRNA, human; D035683:MicroRNAs; D018808:Transcription Factor AP-1; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; C027870:berbamine
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