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Vol. 298, Issue 3, 976-985, September 2001
Departments of Medicine (M.T.Y.-S., C.J.S.) and Biostatistics
(S.-H.J.), Indiana University School of Medicine; Department of Biology
(P.L.C.), Indiana University-Purdue University, Indianapolis, Indiana;
and Lilly Research Laboratories (M.S.M.), Indianapolis, Indiana
Increased cyclooxygenase-2 (COX-2) expression in human pancreatic
adenocarcinomas, as well as the growth-inhibitory effect of
nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, suggests that
NSAIDs may be an effective treatment for pancreatic cancer. Gemcitabine
is currently the most effective chemotherapeutic drug available for
patients with pancreatic cancer, but is only minimally effective
against this aggressive disease. Clearly, other treatment options must
be identified. To design successful therapeutic strategies involving
compounds either alone or in combination with others, it is necessary
to understand their mechanism of action. In the present study, we
evaluated the effects of three NSAIDs (sulindac, indomethacin, and
NS-398) or gemcitabine in two human pancreatic carcinoma cell lines,
BxPC-3 (COX-2-positive) and PaCa-2 (COX-2-negative), previously shown
to be growth-inhibited by these NSAIDs. Effects on cell cycle and
apoptosis were investigated by flow cytometry or Western blotting.
Treatment with NSAIDs or gemcitabine altered the cell cycle phase
distribution as well as the expression of multiple cell cycle
regulatory proteins in both cell lines, but did not induce substantial
levels of apoptosis. Furthermore, we demonstrated that the combination
of the NSAID sulindac or NS-398 with gemcitabine inhibited cell growth
to a greater degree than either compound alone. These results indicate
that the antiproliferative effects of NSAIDs and gemcitabine in
pancreatic tumor cells are primarily due to inhibition of cell cycle
progression rather than direct induction of apoptotic cell death,
regardless of COX-2 expression. In addition, NSAIDs in combination with
gemcitabine may hold promise in the clinic for the treatment of
pancreatic cancer.
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