title: Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma. Thoracic Surgery Directors Association Resident Research Award.
abstract: BACKGROUND
  Malignant mesothelioma is a devastating disease with a poor prognosis. Recent data have shown that insulin-like growth factor-1 receptor (IGF-1R) may play a role in oncogenic signaling. Our aim was to evaluate the effect of a novel IGF-1R inhibitor, NVP-AEW541, on cell growth and IGF associated pathways.
  
  
  METHODS
  Malignant mesothelioma cell lines, H2373 and H2461, previously shown to activate the IGF pathway were grown in culture. The adherent cells, initially plated at 5 x 10(5) cells/plate, were treated for 72 hours, in triplicate, with varying concentration of NVP-AEW541 (0, 1, 5, 10, 20, and 50 microM). Viable cells were counted every 24 hours. Additionally, separate cultures in serum-free medium were treated with NVP-AEW541, then stimulated with IGF and lysates collected for immunoblot analysis.
  
  
  RESULTS
  In both cell lines, 0, 1, 5, and 10 microM showed an inhibitory or static effect, while 20 and 50 microM were cidal. Immunoblot analysis demonstrated that phosphorylation of IGF-1R was inhibited by NVP-AEW541 at higher concentration. Phosphorylation of mitogen-activated protein kinase and Akt, downstream IGF pathway mediators, were also shown to be repressed by drug treatment.
  
  
  CONCLUSIONS
  NVP-AEW541 has a concentration-dependent inhibitory effect on mesothelioma cells in culture. NVP-AEW541 acts by inhibition of IGF-1R phosphorylation. Inhibition effects phosphorylation of downstream mediators in a dose-dependent fashion. Inhibition of the IGF pathway decreases viability of mesothelioma cell culture. Further evaluation of NVP-AEW541, and other selective IGF-1R inhibitors, may play an important role in multimodal treatment of malignant mesothelioma.
authors.affiliation: Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Whitson
authors.forename: Blake A
authors.initials: BA
authors.lastname: Jacobson
authors.forename: Sandra
authors.initials: S
authors.lastname: Frizelle
authors.forename: Manish R
authors.initials: MR
authors.lastname: Patel
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maddaus
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kratzke
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010997:Pleural Neoplasms / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; C501177:NVP-AEW541; D009363:Neoplasm Proteins; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases