title: Arsenic trioxide sensitizes cancer stem cells to chemoradiotherapy. A new approach in the treatment of inoperable glioblastoma multiforme.
abstract: OBJECTIVE
  glioblastoma multiforme (GBM) still bears a very dismal prognosis even with complete resection followed by adjuvant chemoradiation. The aim of the current study was to evaluate in vitro the antitumor efficacy of arsenic trioxide (ATO) in combination with ionizing radiation plus temozolomide and bevacizumab against cultured glioblastoma stem-like cells, as possible way to increase the therapeutic index in patients diagnosed with recurrent, therapy-refractory GBM.
  
  
  METHODS
  stem-like tumor cells isolated from a GBM biopsy were established by cell proliferation assays and upregulation of stem cell markers, as proven by reverse transcription - polymerase chain reaction (RT-PCR). Low concentrations of ATO were added prior to temozolomide, bevacizumab and ionizing irradiation.
  
  
  RESULTS
  molecular analysis showed that cells expressed CXCR4, Oct-3/4 and GAPDH when compared to placental mesenchymal stem cells, as well as nestin, GFAP and neurofilament protein. Low concentrations of ATO led to morphologic differentiation, with fewer stem cells in Go state and differentiation-associated cytochemical features, like increased sensitivity to cytostatic drugs and radiotherapy.
  
  
  CONCLUSIONS
  ATO exposure before conventional postoperative chemoradiotherapy for GBM might increase treatment efficacy. Further in vivo experiments on laboratory animals and analysis of absorption rate and side effects are required.
authors.affiliation: Department of Cancer Immunology - Ion Chiricuta Oncology Institute, Cluj Napoca, Romania. ciprian.tomuleasa@gmail.com
authors.forename: C
authors.initials: C
authors.lastname: Tomuleasa
authors.forename: O
authors.initials: O
authors.lastname: Soritau
authors.forename: G
authors.initials: G
authors.lastname: Kacso
authors.forename: E
authors.initials: E
authors.lastname: Fischer-Fodor
authors.forename: A
authors.initials: A
authors.lastname: Cocis
authors.forename: H
authors.initials: H
authors.lastname: Ioani
authors.forename: T
authors.initials: T
authors.lastname: Timis
authors.forename: M
authors.initials: M
authors.lastname: Petrescu
authors.forename: D
authors.initials: D
authors.lastname: Cernea
authors.forename: P
authors.initials: P
authors.lastname: Virag
authors.forename: A
authors.initials: A
authors.lastname: Irimie
authors.forename: I S
authors.initials: IS
authors.lastname: Florian
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D000068258:Bevacizumab; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000528:radiation effects; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000528:radiation effects*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D019718:Receptors, CXCR4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001152:Arsenicals; C527276:CXCR4 protein, human; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D050814:Octamer Transcription Factor-3; D010087:Oxides; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D019718:Receptors, CXCR4; D000068258:Bevacizumab; D003606:Dacarbazine; D000077237:Arsenic Trioxide; D000077204:Temozolomide