title: Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells.
abstract: BACKGROUND
  Glioblastoma remains one of the most devastating human malignancies, and despite therapeutic advances, there are no drugs that significantly improve the patient survival. Altered expression of the Aurora kinases was found in different malignancies, and their inhibition has been studied in cancer therapy. In this study, we analyzed the expression of Aurora A and Aurora B in glioblastoma samples and also analyzed whether the effects of Aurora kinase inhibition were associated with temozolomide or not on cell lines and primary cultures of glioblastoma.
  
  
  METHODS
  RT-PCR assays were used to determine the mRNA expression in glioblastoma tumor samples and in the cell lines. Cell proliferation was measured by XTT assay, and apoptosis was determined by flow cytometry. Drug combination analyses were made based in Chou-Talalay method. Gamma radiation for clonogenic survival used the doses of 2, 4 and 6 Gy. Changes in Aurora B level were assessed by Western blot analysis.
  
  
  RESULTS
  Aurora A and B were expressed in glioblastoma samples as well as in the glioblastoma cell lines (n = 6). Moreover, ZM447439, a selective Aurora kinase inhibitor, decreased the proliferation separately and synergistically with temozolomide in primary cultures and cell lines of glioblastoma. ZM also enhanced the effects of radiation on the two cell lines studied (U343 and U251), mainly when associated with TMZ in U343 cells. Treatment with ZM induced apoptotic cell death and diminished Aurora B protein level.
  
  
  CONCLUSIONS
  These data suggest that Aurora kinase inhibition may be a target for glioblastoma treatment and could be used as adjuvant to chemo- and radiotherapy.
authors.affiliation: Department of Genetics, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP 14048-900, Brazil. ksborges@usp.br
authors.forename: Kleiton Silva
authors.initials: KS
authors.lastname: Borges
authors.forename: Angel Maurício
authors.initials: AM
authors.lastname: Castro-Gamero
authors.forename: Daniel Antunes
authors.initials: DA
authors.lastname: Moreno
authors.forename: Vanessa
authors.initials: V
authors.lastname: da Silva Silveira
authors.forename: Maria Sol
authors.initials: MS
authors.lastname: Brassesco
authors.forename: Rosane Gomes
authors.initials: RG
authors.lastname: de Paula Queiroz
authors.forename: Harley Francisco
authors.initials: HF
authors.lastname: de Oliveira
authors.forename: Carlos Gilberto
authors.initials: CG
authors.lastname: Carlotti
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000302:isolation & purification; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077204:Temozolomide; D013997:Time Factors
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012334:RNA, Neoplasm; D011838:Radiation-Sensitizing Agents; D003606:Dacarbazine; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000077204:Temozolomide