title: Arsenic trioxide sensitizes glioblastoma to a myc inhibitor.
abstract: Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem-like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti-proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM.
authors.affiliation: Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan; Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Yoshimura
authors.affiliation: Biomedical MR Science Center, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shiino
authors.affiliation: Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Muraki
authors.affiliation: Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Satow
authors.affiliation: Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Saiki
authors.affiliation: Department of Neurosurgery, Shiga Medical Center, Shiga 524-8524, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hojo
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Division of Gene Regulation, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.affiliation: Division of Gene Regulation, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Biomedical MR Science Center, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Inubushi
authors.affiliation: Department of Neurosurgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nozaki
authors.affiliation: Research Institute, Shiga Medical Center, Moriyama 5-4-30, Shiga 524-8524, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tanigaki
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010087:Oxides / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D000970:Antineoplastic Agents; D001152:Arsenicals; D053823:Hedgehog Proteins; D010087:Oxides; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; D013844:Thiazoles; D066246:ErbB Receptors; D000077237:Arsenic Trioxide