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BMS-536924 Sensitizes Human Epithelial Ovarian Cancer Cells to the PARP Inhibitor, 3-aminobenzamide

BMS-536924 Sensitizes Human Epithelial Ovarian Cancer Cells to the PARP Inhibitor, 3-aminobenzamide

Marie-Claude Beauchamp, Ariane Knafo, Amber Yasmeen, Joan M Carboni, Marco M Gottardis, Michael N Pollak, Walter H Gotlieb

Gynecol Oncol. 2009 Nov;115(2):193-8.

PMID: 19699512

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP468740434	BMS-536924		468740-43-4	Price

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