title: Molecular targeting therapy against promyelocytic leukemia protein using arsenic acids in experimental intracranial medulloblastoma.
abstract: Our previous study using human Daoy medulloblastoma cells showed that the promyelocytic leukemia (PML) gene was significantly upregulated (2.5-fold) in cells positive to prominin-1 antigen (CD133), a possible marker for cancer initiating cells. Arsenic trioxide (As(2)O(3)) is known to degrade PML protein and has been used for the treatment of patients with acute PML. In the present study, the effect of PML targeting therapy with As(2)O(3) and cytarabine (Ara-C) on Daoy medulloblastoma cell proliferation was investigated. Daoy cells were pretreated with As(2)O(3) for 6 weeks. The As(2)O(3)-pretreated Daoy cells were cultured in medium containing Ara-C and cell viability was examined. Next, the As(2)O(3)-pretreated Daoy cells were inoculated into the nude mouse brain and the effect of Ara-C on the tumor size was evaluated. A significant increase in chemosensitivity to Ara-C was observed in the As(2)O(3)-pretreated Daoy cells in both in vitro and in vivo conditions. PML and CCND1 (cyclin D1) protein expression of Daoy medulloblastoma cells was downregulated by As(2)O(3) treatment. PML has been proposed as a novel therapeutic target to eradicate quiescent leukemia-initiating cells, and PML-expressing CD133-positive cells are similarly a potential therapeutic target of treatment for medulloblastoma.
authors.affiliation: Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Gu
authors.forename: Naoki
authors.initials: N
authors.lastname: Yokota
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Shinji
authors.initials: S
authors.lastname: Amano
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Koizumi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tokuyama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Namba
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001149:Arsenates / Q000494:pharmacology / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003561:Cytarabine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001149:Arsenates; D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003561:Cytarabine; C070576:PML protein, human; C025657:arsenic acid; D000077237:Arsenic Trioxide