Triptolide sensitizes resistant cholangiocarcinoma cells to TRAIL-induced apoptosis

Anticancer Res. 2006 Jan-Feb;26(1A):259-65.

Abstract

Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) promotes apoptosis by binding to transmembrane receptors. It is known to induce apoptosis in a wide variety of cancer cells, but TRAIL-resistant cancers have also been documented. In this study, the relative resistance of human cholangiocarcinoma (CCA) cell lines against TRAIL-induced apoptosis is reported and the possible potential synergistic effect with triptolide, a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii, in killing TRAIL-resistant CCA cells is investigated.

Materials and methods: Six human CCA cell lines were treated with various concentrations of TRAIL and the resistant cells were identified and subsequently tested for their sensitivity to a combination of TRAIL and triptolide. The susceptibility and resistance of the cells were based on analysis of cytotoxic and apoptotic induction and expression of anti-apoptotic factors (Mcl-1 and cFLIP).

Results: The treatment of TRAIL induced a dose-dependent decrease in cell viability in 4 out of the 6 cell lines. A combination of TRAIL and triptolide enhanced cytotoxicity and apoptosis in these 2 resistant cell lines. The combined treatment enhanced activation of caspase-8 and its downstream signaling processes compared with the treatment with either one alone.

Conclusion: The results presented show that human CCA cells were heterogeneous with respect to susceptibility to TRAIL-induced apoptosis. The combination of TRAIL and triptolide could enhance susceptibility to TRAIL-induced apoptotic killing in these TRAIL-resistant CCA cells, thus offering an alternative approach for the treatment of TRAIL-resistant cholangiocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / administration & dosage
  • Apoptosis Regulatory Proteins / pharmacology*
  • Caspase 8
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / pathology
  • Diterpenes / administration & dosage
  • Diterpenes / pharmacology*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Epoxy Compounds
  • Humans
  • Membrane Glycoproteins / administration & dosage
  • Membrane Glycoproteins / pharmacology*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Phenanthrenes / administration & dosage
  • Phenanthrenes / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Apoptosis Regulatory Proteins
  • Diterpenes
  • Epoxy Compounds
  • Membrane Glycoproteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Phenanthrenes
  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • triptolide
  • Mitogen-Activated Protein Kinase 1
  • CASP8 protein, human
  • Caspase 8
  • Caspases