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

Gynecol Oncol. 2009 Nov;115(2):193-8. doi: 10.1016/j.ygyno.2009.07.009. Epub 2009 Aug 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzamides / administration & dosage
  • Benzamides / pharmacology*
  • Benzimidazoles / administration & dosage
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • DNA Damage
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Humans
  • Oncogene Protein v-akt / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Phosphorylation / drug effects
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyridones / administration & dosage
  • Pyridones / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases / metabolism

Substances

  • BMS 536924
  • Benzamides
  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyridones
  • 3-aminobenzamide
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Receptor, IGF Type 1
  • Oncogene Protein v-akt
  • Ribosomal Protein S6 Kinases