OBJECTIVE: To evaluate the anti-neoplastic activity of BMS-536924, an IGF-1R inhibitor, in epithelial ovarian cancer and its capacity to potentiate the effect of a PARP inhibitor, 3-aminobenzamide. METHODS: OVCAR-3, OVCAR-4, SKOV-3 and TOV-81D cell lines were investigated in low-serum tissue culture conditions (1%FBS). Cytotoxicity assays were performed in quadruplicates using the Alamar colorimetric assay in the presence of BMS-536924 and/or 3-aminobenzamide. The levels of phospho-AKT, phospho-S6, PARP-1 and phospho-H2AX were evaluated by western blotting in the presence of BMS-536924. RESULTS: BMS-536924 induced a time and dose inhibitory effect on cell survival. This effect seemed to be mediated by a reduction of pAKT and pS6 in a dose-dependent manner. The drug also provoked cell death by apoptosis as suggested by the increase in PARP-1 cleavage. It also induces DNA damage as demonstrated by the increased phosphorylation of histone H2AX and the augmentation of the comet tail moment. Finally, BMS-536924 sensitized cells to the effect of the PARP inhibitor, 3-aminobenzamide. CONCLUSION: Our study reinforces the concept that IGF-1R is a good therapeutic target in ovarian cancer. Moreover, it suggests that combination therapy using BMS-536924 with a PARP inhibitor might be an effective strategy to circumvent resistance to treatment in clinical settings.
OBJECTIVE: To evaluate the anti-neoplastic activity of BMS-536924, an IGF-1R inhibitor, in epithelial ovarian cancer and its capacity to potentiate the effect of a PARP inhibitor, 3-aminobenzamide. METHODS: OVCAR-3, OVCAR-4, SKOV-3 and TOV-81D cell lines were investigated in low-serum tissue culture conditions (1%FBS). Cytotoxicity assays were performed in quadruplicates using the Alamar colorimetric assay in the presence of BMS-536924 and/or 3-aminobenzamide. The levels of phospho-AKT, phospho-S6, PARP-1 and phospho-H2AX were evaluated by western blotting in the presence of BMS-536924. RESULTS: BMS-536924 induced a time and dose inhibitory effect on cell survival. This effect seemed to be mediated by a reduction of pAKT and pS6 in a dose-dependent manner. The drug also provoked cell death by apoptosis as suggested by the increase in PARP-1 cleavage. It also induces DNA damage as demonstrated by the increased phosphorylation of histone H2AX and the augmentation of the comet tail moment. Finally, BMS-536924 sensitized cells to the effect of the PARP inhibitor, 3-aminobenzamide. CONCLUSION: Our study reinforces the concept that IGF-1R is a good therapeutic target in ovarian cancer. Moreover, it suggests that combination therapy using BMS-536924 with a PARP inhibitor might be an effective strategy to circumvent resistance to treatment in clinical settings.
Authors: Li-Jeen Mah; Christian Orlowski; Katherine Ververis; Raja S Vasireddy; Assam El-Osta; Tom C Karagiannis Journal: Genome Integr Date: 2011-01-25
Authors: Anthony D Saleh; Brittany A Simone; Juan Palazzo; Jason E Savage; Yuri Sano; Tu Dan; Lianjin Jin; Colin E Champ; Shuping Zhao; Meng Lim; Frederica Sotgia; Kevin Camphausen; Richard G Pestell; James B Mitchell; Michael P Lisanti; Nicole L Simone Journal: Cell Cycle Date: 2013-05-21 Impact factor: 4.534