Synthetic serine protease inhibitor, gabexate mesilate, prevents nuclear factor-kappaB activation and increases TNF-alpha-mediated apoptosis in human pancreatic cancer cells.
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.
Takahashi
Hiroki
H
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, 467-8601, Nagoya, Japan. takahasi@med.nagoya-cu.ac.jp
Funahashi
Hitoshi
H
Sawai
Hirozumi
H
Matsuo
Yoichi
Y
Yamamoto
Minoru
M
Okada
Yuji
Y
Takeyama
Hiromitsu
H
Manabe
Tadao
T
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016670:Gabexate / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016670:Gabexate