Evaluating the Sensitivity of Sporadic Pancreatic Cancer to poly(ADP-ribose) polymerase (PARP) Inhibition (Velaparib, Olaparib, AG14361) as Single Agents and as Chemo-sensitizers

Abstract

After resection of pancreatic cancer local recurrence occurs in 50%-80% of the cases while metastasis develops 75% of the time. Current, adjuvant therapy often consists of gemcitabine, cisplatin and/or 5-fluorouracil which add a modest increase in median survival by 4-5 months. In this study, we treated human pancreatic cancer cells with poly (ADP-ribose) polymerase (PARP) Inhibitors (AG14361, Veliparib and Olaparib) alone or with gemcitabine, cisplatin or 5 - fluorouracil. Methods: CFPAC-1 and BXPC-3, HPAC human pancreatic cancer cell lines were treated for 72 hours with PARP inhibitors alone or in combination with gemcitabine, cisplatin, or 5 - fluorouracil. Validated MTT assays were used to form dose response curves from which the IC50 values were calculated. Results: The PARP1 IC50 values for CFPAC-1, BXPC-3 and HPAC pancreatic cancer cell lines were AG14361 (14.3 M, 12.7 M, 38.3 M), Veliparib (52.6 M, 100.9 M 102.0 M) and Olaparib (79.5 M, 184.8 M, 200.2 M). The IC50 values of cisplatin, were decreased up to 60 fold in the presence of clinically relevant amounts of PARP inhibitor while 5-flourouracil IC50 values were decreased up to 6000 fold in the presence of clinically relevant amounts of PARP inhibitor. Gemcitabine was inhibited up to 73% by PARP inhibitors. Conclusions: Sporadic human pancreatic cancer cells are sensitive to PARP inhibition. PARP inhibitors significantly enhanced the cytotoxicity of cisplatin and 5-fluorouracil while inhibiting gemcitabine. There is little correlation between endogenous PARP activity and the effectiveness of PARP inhibitors.