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Research ArticleCELLULAR AND MOLECULAR

Cell Cycle Effects of Nonsteroidal Anti-Inflammatory Drugs and Enhanced Growth Inhibition in Combination with Gemcitabine in Pancreatic Carcinoma Cells

Michele T. Yip-Schneider, Christopher J. Sweeney, Sin-Ho Jung, Pamela L. Crowell and Mark S. Marshall
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 976-985;
Michele T. Yip-Schneider
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Christopher J. Sweeney
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Sin-Ho Jung
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Pamela L. Crowell
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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.

Footnotes

  • This study was supported by a research grant supplied by Lilly Research Laboratories.

  • Abbreviations:
    NSAID
    nonsteroidal anti-inflammatory drug
    COX
    cyclooxygenase
    PI
    propidium iodide
    CI
    combination index
    PBS
    phosphate-buffered saline
    DMSO
    dimethylsulfoxide
    TdT
    terminal deoxynucleotidyl transferase
    FITC
    fluorescein isothiocyanate
    • Received March 2, 2001.
    • Accepted May 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleCELLULAR AND MOLECULAR

Cell Cycle Effects of Nonsteroidal Anti-Inflammatory Drugs and Enhanced Growth Inhibition in Combination with Gemcitabine in Pancreatic Carcinoma Cells

Michele T. Yip-Schneider, Christopher J. Sweeney, Sin-Ho Jung, Pamela L. Crowell and Mark S. Marshall
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 976-985;

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Research ArticleCELLULAR AND MOLECULAR

Cell Cycle Effects of Nonsteroidal Anti-Inflammatory Drugs and Enhanced Growth Inhibition in Combination with Gemcitabine in Pancreatic Carcinoma Cells

Michele T. Yip-Schneider, Christopher J. Sweeney, Sin-Ho Jung, Pamela L. Crowell and Mark S. Marshall
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 976-985;
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