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

Abstract

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