bms-536924 and 3-aminobenzamide

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.. 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.. 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.. 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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Benzimidazoles; Cell Line, Tumor; DNA Damage; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Oncogene Protein v-akt; Ovarian Neoplasms; Phosphorylation; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pyridones; Receptor, IGF Type 1; Ribosomal Protein S6 Kinases