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

BMC Res Notes. 2016 Mar 1:9:134. doi: 10.1186/s13104-016-1919-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carboplatin / pharmacology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology*
  • Drug Combinations
  • Drug Synergism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology*
  • Receptor, Insulin / antagonists & inhibitors
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Signal Transduction
  • Triazines / pharmacology*

Substances

  • Antineoplastic Agents
  • BMS 754807
  • Drug Combinations
  • Histones
  • IGF1 protein, human
  • Pyrazoles
  • Triazines
  • Insulin-Like Growth Factor I
  • Carboplatin
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • Caspase 3
  • Cisplatin