Inhibition of the phosphatidylinositol 3′-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac

Michele Yip-Schneider, Chad A. Wiesenauer, C. Schmidt

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25 Citations (Scopus)

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidylinositol 3′-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 μmol/L) and/or LY294002 (1 to 100 μmol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 μmol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent asssay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac.

Original languageEnglish
Pages (from-to)354-363
Number of pages10
JournalJournal of Gastrointestinal Surgery
Volume7
Issue number3
DOIs
StatePublished - Mar 2003

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Phosphatidylinositol 3-Kinase
Sulindac
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Anti-Inflammatory Agents
Cell Cycle
Pharmaceutical Preparations
Pancreatic Neoplasms
Growth
Phosphorylation
Apoptosis
Cell Line
Immunosorbents
DNA Fragmentation
Cell- and Tissue-Based Therapy
Protein Kinases
Pancreatic Carcinoma
Flow Cytometry
Cell Count
Survival
Enzymes

Keywords

  • Akt
  • NSAIDs
  • Pancreatic cancer
  • PI3′-kinase

ASJC Scopus subject areas

  • Surgery

Cite this

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title = "Inhibition of the phosphatidylinositol 3′-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac",
abstract = "Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidylinositol 3′-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 μmol/L) and/or LY294002 (1 to 100 μmol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 μmol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent asssay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac.",
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author = "Michele Yip-Schneider and Wiesenauer, {Chad A.} and C. Schmidt",
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AU - Yip-Schneider, Michele

AU - Wiesenauer, Chad A.

AU - Schmidt, C.

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N2 - Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidylinositol 3′-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 μmol/L) and/or LY294002 (1 to 100 μmol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 μmol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent asssay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac.

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