title: Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines.
abstract: OBJECTIVE
  The role of the insulin-like growth factor (IGF) system in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR signaling pathways. The aim of the present study was to investigate the anti-proliferative activity of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines.
  
  
  METHODS
  Type I (ECC-1, Ishikawa) and Type II (USPC-1, USPC-2) endometrial cancer cell lines were treated with NVP-AEW541 in the presence of IGF-I, and the following parameters were measured: IGF-IR, AKT and ERK phosphorylation, apoptosis, proliferation, cell cycle progression and IGF-IR internalization.
  
  
  RESULTS
  Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated, whereas it abolished AKT and ERK phosphorylation preferentially in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor.
  
  
  CONCLUSIONS
  Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Attias-Geva
authors.forename: Itay
authors.initials: I
authors.lastname: Bentov
authors.forename: Ami
authors.initials: A
authors.lastname: Fishman
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
authors.forename: Ilan
authors.initials: I
authors.lastname: Bruchim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C501177:NVP-AEW541; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin