title: Synergistic killing of colorectal cancer cells by oxaliplatin and ABT-737.
abstract: BACKGROUND
  Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer (CRC). Our previous work shows that oxaliplatin induces the pro-apoptotic protein Noxa in CRC cells. The Bcl2-inhibitor ABT-737 is particularly effective in cells with high Noxa levels. Therefore, we tested whether oxaliplatin and ABT-737 display synergy in killing CRC cells.
  
  
  METHODS
  A panel of CRC cell lines was treated with oxaliplatin and ABT-737, either alone or in combination. Apoptosis was measured by FACS analysis of sub-G1 DNA content and by Western blot analysis of caspase-3 processing. Noxa expression was suppressed by lentiviral RNA interference.
  
  
  RESULTS
  Oxaliplatin and ABT-737 displayed a strong synergistic apoptotic response, which was dependent on wildtype TP53 and oncogenic KRAS. TP53 and KRAS were required for drug-induced Noxa expression and this was essential for tumor cell apoptosis. Oxaliplatin, but not ABT-737, induced p53 accumulation, but both drugs stimulated Noxa expression. Combination treatment of mice with subcutaneous tumor xenografts drastically reduced tumor volume, while single drug treatment had no effect.
  
  
  CONCLUSIONS
  ABT-737 synergizes with oxaliplatin to kill colorectal cancer cells. This requires induction of Noxa by wildtype TP53 and oncogenic KRAS. Future studies should explore the anti-tumor efficacy of this drug combination in mouse models for spontaneous CRC development and in patient-derived tumor cell cultures and xenografts.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, The Netherlands.
authors.forename: Daniëlle A E
authors.initials: DA
authors.lastname: Raats
authors.forename: Menno T
authors.initials: MT
authors.lastname: de Bruijn
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Emmink
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel-Rinkes
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D004357:Drug Synergism; D051379:Mice; D008954:Models, Biological; D009596:Nitrophenols / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D009944:Organoplatinum Compounds; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D053148:Caspase 3