Insulin-like growth factor receptor I targeting in epithelial ovarian cancer.
OBJECTIVE
Preclinical evaluation of the anti-neoplastic activity of an insulin-like growth factor I receptor (IGF-IR) kinase inhibitor in ovarian cancer.


METHODS
The OVCAR-3 and OVCAR-4 cell lines were investigated under serum-free tissue culture conditions. IGF-I and IGF-II production were evaluated by standard ELISA and immunohistochemistry. IGF-IR expression and protein levels were evaluated by Western blotting. Cytotoxicity assays were performed in triplicates using the Alamar colorimetric assay. Apoptosis was evaluated by flow cytometry and by Western blotting for PARP.


RESULTS
The OVCAR-3 and OVCAR-4 cell lines produce IGF-I and IGF-II, and express IGF-IR, detectable by Western blotting, supporting the existence of an autocrine loop. The existence of this loop justified studies of NVP-AEW541, a small molecular weight inhibitor of the IGF-IR kinase. We observed growth inhibition of the ovarian cancer cell lines, with IC50 between 5 and 15 microM. We also observed that NVP-AEW541 sensitized cells to cisplatin in vitro. Western blotting demonstrated that NVP-AEW541 induced apoptosis at the concentrations that were used in the cytotoxicity assays, and decreased the concentration of the phosphorylated AKT signaling protein downstream of the IGF-IR.


CONCLUSIONS
IGF-IR is a potential new molecular target in ovarian cancer. The anti-neoplastic activity of NVP-AEW541 in ovarian cancer was observed at concentrations higher than those previously reported for multiple myeloma, suggesting the possibility that a portion of the observed anti-neoplastic activity could involve targets other than the IGF-IR. Experiments are being conducted to investigate the cytotoxicity profile in vivo and the clinical relevance of NVP-AEW541 in ovarian cancer treatment.
Gotlieb
Walter H
WH
Division of Gynecologic Oncology, McGill University, Montreal, Quebec, Canada. walter.gotlieb@mcgill.ca
Bruchim
Ilan
I
Gu
Jing
J
Shi
Ying
Y
Camirand
Anne
A
Blouin
Marie-José
MJ
Zhao
Yunhua
Y
Pollak
Michael N
MN
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; 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 / Q000096:biosynthesis / Q000378:metabolism*
C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin