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

Publication ,  Journal Article
Yip-Schneider, MT; Sweeney, CJ; Jung, SH; Crowell, PL; Marshall, MS
Published in: J Pharmacol Exp Ther
September 2001

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.

Duke Scholars

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

September 2001

Volume

298

Issue

3

Start / End Page

976 / 985

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sulindac
  • Prostaglandin-Endoperoxide Synthases
  • Pharmacology & Pharmacy
  • Pancreatic Neoplasms
  • Membrane Proteins
  • Male
  • Isoenzymes
  • Humans
  • Gemcitabine
 

Citation

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Yip-Schneider, M. T., Sweeney, C. J., Jung, S. H., Crowell, P. L., & Marshall, M. S. (2001). Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther, 298(3), 976–985.
Yip-Schneider, M. T., C. J. Sweeney, S. H. Jung, P. L. Crowell, and M. S. Marshall. “Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells.J Pharmacol Exp Ther 298, no. 3 (September 2001): 976–85.
Yip-Schneider MT, Sweeney CJ, Jung SH, Crowell PL, Marshall MS. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther. 2001 Sep;298(3):976–85.
Yip-Schneider MT, Sweeney CJ, Jung SH, Crowell PL, Marshall MS. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther. 2001 Sep;298(3):976–985.

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

September 2001

Volume

298

Issue

3

Start / End Page

976 / 985

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sulindac
  • Prostaglandin-Endoperoxide Synthases
  • Pharmacology & Pharmacy
  • Pancreatic Neoplasms
  • Membrane Proteins
  • Male
  • Isoenzymes
  • Humans
  • Gemcitabine