title: Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in pancreatic cancer cells but not bone marrow precursor cells.
abstract: BACKGROUND
  Amplification of aurora kinase A (AK-A) overrides the mitotic spindle assembly checkpoint, inducing resistance to taxanes. RNA interference targeting AK-A in human pancreatic cancer cell lines enhanced taxane chemosensitivity. In this study, a novel AK-A inhibitor, CYC3, was investigated in pancreatic cancer cell lines, in combination with paclitaxel.
  
  
  METHODS
  Western blot, flow cytometry and immunostaining were used to investigate the specificity of CYC3. Sulforhodamine B staining, time-lapse microscopy and colony-formation assays were employed to evaluate the cytotoxic effect of CYC3 and paclitaxel. Human colony-forming unit of granulocyte and macrophage (CFU-GM) cells were used to compare the effect in tumour and normal tissue.
  
  
  RESULTS
  CYC3 was shown to be a specific AK-A inhibitor. Three nanomolar paclitaxel (growth inhibition 50% (GI(50)) 3 nM in PANC-1, 5.1 nM in MIA PaCa-2) in combination with 1 μM CYC3 (GI(50) 1.1 μM in MIA PaCa2 and 2 μM in PANC-1) was synergistic in inhibiting pancreatic cell growth and causing mitotic arrest, achieving similar effects to 10-fold higher concentrations of paclitaxel (30 nM). In CFU-GM cells, the effect of the combination was simply additive, displaying significantly less myelotoxicity compared with high concentrations of paclitaxel (30 nM; 60-70% vs 100% inhibition).
  
  
  CONCLUSIONS
  The combination of lower doses of paclitaxel and CYC3 merits further investigation with the potential for an improved therapeutic index in vivo.
authors.affiliation: Department Of Oncology, University of Cambridge, Cambridge CB2 0RE, UK. yao.lin@cancer.org.uk
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: F M
authors.initials: FM
authors.lastname: Richards
authors.forename: B-F
authors.initials: BF
authors.lastname: Krippendorff
authors.forename: J L
authors.initials: JL
authors.lastname: Bramhall
authors.forename: J A
authors.initials: JA
authors.lastname: Harrington
authors.forename: T E
authors.initials: TE
authors.lastname: Bapiro
authors.forename: A
authors.initials: A
authors.lastname: Robertson
authors.forename: D
authors.initials: D
authors.lastname: Zheleva
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D055014:Granulocyte-Macrophage Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel