Synthetic Serine Protease Inhibitor, Gabexate Mesilate, Prevents Nuclear Factor-κB Activation and Increases TNF-α-Mediated Apoptosis in Human Pancreatic Cancer Cells

Gabexate mesilate (GM), a synthetic serine protease inhibitor, suppresses nuclear factor-κB (NF-κB) activity in human monocytes or human umbilical vein endothelial cells (HUVECs). In this study we examine whether GM also suppresses NF-κB activation and induces apoptosis in human pancreatic cancer cell lines. The addition of tumor necrosis factor α (TNF-α) did not change the rates of growth of BxPC-3 and MIA PaCa-2. However, in the presence of GM and TNF-α, proliferation decreased in a dose-dependent manner. GM- and TNF-α-treated cells exhibited morphologic changes indicative of apoptosis, including chromatin condensation and nuclear fragmentation. The NF-κB activity of both cell lines was increased by the addition of TNF-α, while TNF-α-induced NF-κB activity was suppressed by prestimulation with GM in a dose-dependent manner. Caspase 3 and 7 activity was significantly increased by TNF-α with GM stimulation. Furthermore, GM also suppressed the invasive potential of both cell lines. These results indicate that GM inhibits TNF-α-induced NF-κB activation and enhances apoptosis in human pancreatic cancer cell lines.