BMS-536924 sensitizes human epithelial ovarian cancer cells to the PARP inhibitor, 3-aminobenzamide.
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.


CONCLUSIONS
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.
Beauchamp
Marie-Claude
MC
Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Knafo
Ariane
A
Yasmeen
Amber
A
Carboni
Joan M
JM
Gottardis
Marco M
MM
Pollak
Michael N
MN
Gotlieb
Walter H
WH
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
C504983:BMS 536924; D001549:Benzamides; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011728:Pyridones; C025160:3-aminobenzamide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt; D019893:Ribosomal Protein S6 Kinases