The chemosensitizing properties of iniparib in combination with gemcitabine (G) and carboplatin (C) in OVCAR-3 ovarian adenocarcinoma.

Abstract

e15532 Background: Iniparib, a novel agent with PARP inhibitory activity, has demonstrated anticancer activity when combined with DNA-damaging chemotherapy in clinical and preclinical settings. The objective of this study was to evaluate the activity of iniparib in combination with G and C in ovarian adenocarcinoma. Methods: The chemosensitizing properties of a single dose of iniparib were evaluated in combination with G and C against OVCAR-3 ovarian adenocarcinoma 72 hours after treatment.Cell proliferation was evaluated with FACS-based cell cycle analysis, including DNA staining and bromodeoxyuridine (BrdU) incorporation. Apoptotic cells were quantified by TUNEL staining. Results: FACS analysis showed that iniparib potentiated apoptosis induced by G or C in OVCAR-3 cells (Table). Combination of iniparib with G+C enhanced apoptosis and induced S-phase cell cycle arrest in OVCAR-3 cells. Conclusions: These data demonstrate the potentiation of the antiproliferative and pro-apoptotic activities of C and G by iniparib in OVCAR-3 cells. They support the clinical investigation of iniparib in combination with these DNA-damaging agents. Treatment Sub-G1* G1* BrdU(-) S* S* G2/M* TUNEL(+) Vehicle (control) 3.42 48.34 2.85 31.11 14.29 5.5 Iniparib (0 uM) + C (0 uM) +G (0 nM) 3.42 48.24 2.70 31.43 14.21 5.5 +G (1 nM) 4.28 43.38 2.85 38.70 10.79 7.4 +G (2 nM) 6.47 27.81 3.24 54.80 7.68 9.2 Iniparib (0 uM) + C (5 uM) +G (0 nM) 11.87 15.07 6.30 34.37 32.40 14.3 +G (1 nM) 9.47 13.48 5.66 39.20 32.20 13.1 +G (2 nM) 9.11 11.26 5.53 40.12 33.98 12.0 Iniparib (0 uM) + C (10 uM) +G (0 nM) 17.06 16.55 9.35 31.45 25.59 14.8 +G (1 nM) 16.44 16.86 12.41 32.26 22.03 17.7 +G (2 nM) 20.43 21.98 11.46 26.73 19.40 18.8 Iniparib (50 uM) + C (0 uM) +G (0 nM) 4.75 42.31 4.23 32.30 16.41 14.2 +G (1 nM) 5.51 32.96 4.59 44.18 12.76 17.2 +G (2 nM) 7.84 21.38 5.09 54.58 11.10 25.1 Iniparib (50 uM) + C (5 uM) +G (0 nM) 11.07 13.52 11.37 30.02 34.02 39.2 +G (1 nM) 11.78 14.34 12.70 34.94 26.23 41.0 +G (2 nM) 11.09 13.76 10.68 36.76 27.72 42.5 Iniparib (50 uM) + C (10 uM) +G (0 nM) 14.01 16.16 14.52 30.67 24.64 49.5 +G (1 nM) 15.87 19.94 17.90 28.59 17.70 53.3 +G (2 nM) 12.60 17.99 14.43 34.04 20.93 50.3 * Data represent % cells from total population of viable cells.