Synergistic cytotoxic effect of TRAIL and gemcitabine in pancreatic cancer cells

Anticancer Res. Jan-Feb 2003;23(1A):251-8.

Abstract

Background: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a novel member of the TNF family and triggers apoptosis in a variety of malignant cells.

Materials and methods: We assessed the antitumour activity of TRAIL in six human pancreatic cancer cell lines by measuring apoptosis with sulforhodamine B cytotoxicity assays, DAPI staining and FACScans.

Results: All six cell lines were sensitive to TRAIL-induced apoptosis. The expression levels of TRAIL receptors R1, R2, R3 and R4 did not correlate with TRAIL sensitivity. Simultaneous treatment with TRAIL and the chemotherapeutic agent gemcitabine had a synergistic effect. Caspase-8 and -3 activities were increased by TRAIL treatment and apoptosis was largely blocked by caspase-8 and -3 inhibitors.

Conclusion: Apoptotic cell death can be induced in pancreatic cancer cells by TRAIL treatment and this may be mediated through activation of caspases-8 and -3. Gemcitabine significantly increased the antitumour effect of TRAIL, suggesting novel therapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Humans
  • Membrane Glycoproteins / administration & dosage
  • Membrane Glycoproteins / pharmacology*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Deoxycytidine
  • gemcitabine
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases