title: MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation.
abstract: OBJECTIVE
  To determine whether MLN8054, an Aurora kinase A (Aurora-A) inhibitor causes radiosensitization in androgen-insensitive prostate cancer cells in vitro and in vivo.
  
  
  METHODS
  In vitro studies consisted of culturing PC3 and DU145 prostate cancer cells and then immunoblotting Aurora A and phospho-Aurora A after radiation and/or nocodazole with MLN8054. Phases of the cell cycle were measured with flow cytometry. PC3 and DU145 cell lines were measured for survival after treatment with MLN8054 and radiation. Immunofluorescence measured γ-H2AX in the PC3 and DU145 cells after treatment. In vivo studies looked at growth delay of PC3 tumor cells in athymic nude mice. PC3 cells grew for 6 to 8 days in mice treated with radiation, MLN8054, or combined for 7 more days. Tumors were resected and fixed on paraffin and stained for von Willebrand factor, Ki67, and caspase-3.
  
  
  RESULTS
  In vitro inhibition of Aurora-A by MLN8054 sensitized prostate cancer cells, as determined by dose enhancement ratios in clonogenic assays. These effects were associated with sustained DNA double-strand breaks, as evidenced by increased immunofluorescence for γ-H2AX and significant G2/M accumulation and polyploidy. In vivo, the addition of MLN8054 (30 mg/kg/day) to radiation in mouse prostate cancer xenografts (PC3 cells) significantly increased tumor growth delay and apoptosis (caspase-3 staining), with reduction in cell proliferation (Ki67 staining) and vascular density (von Willebrand factor staining).
  
  
  CONCLUSIONS
  MLN8054, a novel small molecule Aurora-A inhibitor showed radiation sensitization in androgen-insensitive prostate cancer in vitro and in vivo. This warrants the clinical development of MLN8054 with radiation for prostate cancer patients.
authors.affiliation: Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232-5671, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Moretti
authors.forename: Kenneth
authors.initials: K
authors.lastname: Niermann
authors.forename: Stephen
authors.initials: S
authors.lastname: Schleicher
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Giacalone
authors.forename: Vinod
authors.initials: V
authors.lastname: Varki
authors.forename: Kwang Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Kopsombut
authors.forename: Dae Kwang
authors.initials: DK
authors.lastname: Jung
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
mesh_terms: D000728:Androgens / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001552:Benzazepines / Q000627:therapeutic use*; D053148:Caspase 3 / Q000032:analysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006657:Histones / Q000032:analysis; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015739:Nocodazole / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
chemical_list: D000728:Androgens; D001552:Benzazepines; C468783:H2AX protein, human; D006657:Histones; D019394:Ki-67 Antigen; C518940:MLN8054; D011838:Radiation-Sensitizing Agents; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D015739:Nocodazole