title: BMS-754807 is cytotoxic to non-small cell lung cancer cells and enhances the effects of platinum chemotherapeutics in the human lung cancer cell line A549.
abstract: BACKGROUND
  Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential target for lung cancer treatment, however, clinical trials to date have provided disappointing results. Further research is needed to identify if certain patients would benefit from IGF-IR targeted therapies and the ideal approach to incorporate IGF-IR targeted agents with current therapies.
  
  
  METHODS
  The dual IGF-IR/insulin receptor inhibitor, BMS-754807, was evaluated alone and in combination with platinum-based chemotherapeutics in two human non-small cell lung cancer (NSCLC) cell lines. Cell survival was determined using WST-1 assays and drug interaction was evaluated using Calcusyn software. Proliferation and apoptosis were determined using immunofluorescence for phospho-histone H3 and cleaved caspase 3, respectively.
  
  
  RESULTS
  Treatment with BMS-754807 alone reduced cell survival and wound closure while enhancing apoptosis in both human lung cancer cell lines. These effects appear to be mediated through IGF-IR/IR signaling and, at least in part, through the PI3K/AKT pathway as administration of BMS-754807 to A549 or NCI-H358 cells significantly suppressed IGF-IR/IR and AKT phosphorylation. In addition of BMS-754807 enhanced the cytotoxic effects of carboplatin or cisplatin in a synergistic manner when given simultaneously to A549 cells.
  
  
  CONCLUSIONS
  BMS-754807 may be an effective therapeutic agent for the treatment of NSCLC, particularly in lung cancer cells expressing high levels of IGF-IR.
authors.affiliation: Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. sfranks@uoguelph.ca.
authors.forename: S Elizabeth
authors.initials: SE
authors.lastname: Franks
authors.affiliation: Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. rjones12@uoguelph.ca.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Jones
authors.affiliation: Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. rbriah@uoguelph.ca.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Briah
authors.affiliation: Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. paytonmu@uoguelph.ca.
authors.forename: Payton
authors.initials: P
authors.lastname: Murray
authors.affiliation: Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. rmoorehe@uoguelph.ca.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Moorehead
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C545990:BMS 754807; D004338:Drug Combinations; D006657:Histones; C583557:IGF1 protein, human; D011720:Pyrazoles; D014227:Triazines; D007334:Insulin-Like Growth Factor I; D016190:Carboplatin; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin