PURPOSE: 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. CONCLUSION: Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.
PURPOSE: 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. CONCLUSION: Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.
Authors: Almudena Valenciano; Luis Alberto Henríquez-Hernández; Mercedes Moreno; Marta Lloret; Pedro Carlos Lara Journal: Transl Oncol Date: 2012-02-01 Impact factor: 4.243
Authors: Runmin Wei; Immaculata De Vivo; Sijia Huang; Xun Zhu; Harvey Risch; Jason H Moore; Herbert Yu; Lana X Garmire Journal: Oncotarget Date: 2016-08-23