title: Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells.
abstract: Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Lai
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
authors.forename: Ping-Hsiao
authors.initials: PH
authors.lastname: Shih
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Yao
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan; Cancer Center, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wang-Peng
authors.affiliation: Division of Neurosurgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tai-Ngar
authors.initials: TN
authors.lastname: Lui
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Suang-En
authors.initials: SE
authors.lastname: Chuang
authors.affiliation: Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tsai-Shu
authors.initials: TS
authors.lastname: Hu
authors.affiliation: Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tung-Yuan
authors.initials: TY
authors.lastname: Lai
authors.affiliation: Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Gi-Ming
authors.initials: GM
authors.lastname: Lai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D000077204:Temozolomide; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D001713:Biphenyl Compounds; D003606:Dacarbazine; D018398:Homeodomain Proteins; D017705:Lignans; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000077204:Temozolomide; D000072056:Transcription Factor HES-1; C499374:NOTCH3 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C078493:HES1 protein, human