Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells

Michele Yip-Schneider, Christopher J. Sweeney, Sin Ho Jung, Pamela L. Crowell, Mark S. Marshall

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Abstract

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.

Original languageEnglish
Pages (from-to)976-985
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number3
StatePublished - 2001

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gemcitabine
Cell Cycle
Anti-Inflammatory Agents
Cyclooxygenase 2
Growth
Pharmaceutical Preparations
Pancreatic Neoplasms
Sulindac
Apoptosis
Therapeutics
Cell Line
Cell Cycle Proteins
Pancreatic Carcinoma
Drug Combinations
Indomethacin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. / Yip-Schneider, Michele; Sweeney, Christopher J.; Jung, Sin Ho; Crowell, Pamela L.; Marshall, Mark S.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 298, No. 3, 2001, p. 976-985.

Research output: Contribution to journalArticle

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