title: Antitumour activity of AMG 900 alone or in combination with histone deacetylase inhibitor SaHa on medulloblastoma cell lines.
abstract: OBJECTIVE
  Medulloblastoma (MB) is the most common malignant childhood brain tumour. Aurora kinases are essential for cell division and are primarily active during mitosis. Recently, the combination of aurora kinases inhibitors (iAURK) and histone deacetylase inhibitors (iHDAC) has shown potential antitumour effects and had significant biological effects in preclinical cancer models. In this study, we analysed the effects of the pan-aurora kinases inhibitor AMG 900 alone or in combination with the iHDAC SaHa (Vorinostat) on paediatric MB cell lines (UW402, UW473 and ONS-76).
  
  
  METHODS
  Cell proliferation was measured by XTT assay, apoptosis was determined by flow cytometry and clonogenic capacity was studied. qRT-PCR assays were used to determine the mRNA expression in MB cell lines after treatment. Drug combination analyses were made based on Chou-Talalay method.
  
  
  RESULTS
  AMG 900 caused the inhibition of cell proliferation, diminution of clonogenic capacity and increased the apoptosis rate in cell lines (P < 0.05). A synergistic effect in the AMG900-SaHa combination was evidenced on the inhibition of cell proliferation in all cell lines, especially in sequential drug treatment. Moreover, the combination of these drugs reached 100% of the inhibition in colony formation (synergistic effect). The treatment with AMG 900 increased the p21 and GDF15 expression, but did not alter the TP53 in one of the cell lines.
  
  
  CONCLUSIONS
  These results indicate that AMG 900 may be a promising drug for the adjuvant treatment of MB, mainly when combined with iHDAC.
authors.forename: Lenisa
authors.initials: L
authors.lastname: Geron
authors.forename: Kleiton Silva
authors.initials: KS
authors.lastname: Borges
authors.forename: Augusto Faria
authors.initials: AF
authors.lastname: Andrade
authors.forename: Veridiana Kill
authors.initials: VK
authors.lastname: Suazo
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008527:Medulloblastoma / Q000188:drug therapy* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat
keywords: AMG900,; Aurora-kinase,; Combination; Medulloblastoma,; SaHa (Vorinostat),