title: Glycolytic inhibitor 2-deoxyglucose simultaneously targets cancer and endothelial cells to suppress neuroblastoma growth in mice.
abstract: Neuroblastoma is characterized by a wide range of clinical manifestations and associated with poor prognosis when there is amplification of MYCN oncogene or high expression of Myc oncoproteins. In a previous in vitro study, we found that the glycolytic inhibitor 2-deoxyglucose (2DG) could suppress the growth of neuroblastoma cells, particularly in those with MYCN amplification. In this study, we established a mouse model of neuroblastoma xenografts with SK-N-DZ and SK-N-AS cells treated with 2DG by intraperitoneal injection twice a week for 3 weeks at 100 or 500 mg/kg body weight. We found that 2DG was effective in suppressing the growth of both MYCN-amplified SK-N-DZ and MYCN-non-amplified SK-N-AS neuroblastoma xenografts, which was associated with downregulation of HIF-1α, PDK1 and c-Myc, and a reduction in the number of tumor blood vessels. In vitro study showed that 2DG can suppress proliferation, cause apoptosis and reduce migration of murine endothelial cells, with inhibition of the formation of lamellipodia and filopodia and disorganization of F-actin filaments. The results suggest that 2DG might simultaneously target cancer cells and endothelial cells in the neuroblastoma xenografts in mice regardless of the status of MYCN amplification, providing a potential therapeutic opportunity to use 2DG or other glycolytic inhibitors for the treatment of patients with refractory neuroblastoma.
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Chi-Mei Medical Center, Tainan 710, Taiwan Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
authors.forename: Shuo-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Lin
authors.affiliation: The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan Department of Internal and Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
authors.forename: Ting-Ya
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.affiliation: The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Tsu-Kung
authors.initials: TK
authors.lastname: Lin
authors.affiliation: The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liou
authors.affiliation: The Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan The Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan jhchuang@cgmh.org.tw.
authors.forename: Jiin-Haur
authors.initials: JH
authors.lastname: Chuang
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D006019:Glycolysis / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000199:Actins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631433:Pdk1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases
keywords: 2-deoxyglucose; Endothelial cell; MYCN amplification; Neuroblastoma; Xenograft