Pancreatic Cancer Cell Genetics and Signaling Response to Treatment Correlate with Efficacy of Gemcitabine-Based Molecular Targeting Strategies

Introduction Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-κB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. Materials and Methods PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay. Results Each agent dose-dependently decreased proliferation. All cells decreased NF-κB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-κB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. Conclusions These results demonstrate differences in treatment efficacy, which correlate with the cell’s signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.