title: Combined Treatment of ATRA with Epigenetic Drugs Increases Aggressiveness of Glioma Xenografts.
abstract: OBJECTIVE
  Recently, anti-tumourigenic effects of all-trans-retinoic-acid (ATRA) on glioblastoma stem cells were demonstrated. Therefore we investigated if these beneficial effects could be enhanced by co-medication with epigenetic drugs such as the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) or the DNA-methyltransferase inhibitor 5-aza-2'deoxycytidine (5-AZA).
  
  
  METHODS
  Glioma stem cell xenografts were treated for 42 days with ATRA plus SAHA or ATRA plus 5-AZA or the correspondent monotherapies. Tumour sizes, histological features, proliferation and apoptosis rates were assessed.
  
  
  RESULTS
  Neither SAHA nor 5-AZA were able to enhance the anti-tumourigenic effect of ATRA. Instead, tumours became more aggressive. Combination of ATRA plus 5-AZA increased tumour size (p<0.05) and induced more frequent and larger necroses (p<0.05) and tumours were more invasive (p<0.05) in comparison to controls. A similar trend was observed for the combination of ATRA plus SAHA.
  
  
  CONCLUSIONS
  Combining ATRA with epigenetic drug therapies led to the unwanted opposite effect and increased aggressiveness of glioma xenografts, arguing against future clinical applications of such combinations.
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmoch
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Gal
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mock
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mossemann
authors.affiliation: Institute of Medical Biometry and Informatics, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Institute of Medical Biometry and Informatics, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Division of Tumor Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, Hamamatsu Tissue Imaging and Analysis Center, University of Heidelberg, Heidelberg, Germany H.Mende@med.uni-heidelberg.de.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001374:Azacitidine / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D057890:Epigenomics; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000627:therapeutic use; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014212:Tretinoin / Q000009:adverse effects* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014212:Tretinoin; D000077337:Vorinostat; D001374:Azacitidine
keywords: 5-AZA; ATRA; SAHA; stem-like glioma cells