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Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway.

Abstract
The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) causes cancer cell death, but many cancers, including pancreatic cancer, are resistant to TRAIL therapy. A combination of TRAIL and the diterpene triepoxide, triptolide, is effective in inducing pancreatic cancer cell death. Triptolide increases levels of death receptor DR5 and decreases the pro-survival FLICE-like inhibitory protein (c-FLIP), which contribute to the activation of caspase-8. This combination further causes both lysosomal and mitochondrial membrane permeabilization, resulting in cell death. Our study provides a mechanism by which triptolide sensitizes TRAIL resistant cells, which may become a novel therapeutic strategy against pancreatic cancer.
AuthorsZhiyu Chen, Veena Sangwan, Sulagna Banerjee, Rohit Chugh, Vikas Dudeja, Selwyn M Vickers, Ashok K Saluja
JournalCancer letters (Cancer Lett) Vol. 348 Issue 1-2 Pg. 156-66 (Jun 28 2014) ISSN: 1872-7980 [Electronic] Ireland
PMID24662747 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents, Alkylating
  • BAX protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Diterpenes
  • Epoxy Compounds
  • Phenanthrenes
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • bcl-2-Associated X Protein
  • triptolide
  • CASP8 protein, human
  • Caspase 8
Topics
  • Animals
  • Antineoplastic Agents, Alkylating (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • BH3 Interacting Domain Death Agonist Protein (metabolism)
  • CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
  • Caspase 8 (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Diterpenes (pharmacology)
  • Drug Resistance, Neoplasm (drug effects)
  • Enzyme Activation
  • Epoxy Compounds (pharmacology)
  • Humans
  • Lysosomes (drug effects, metabolism)
  • Mice
  • Mitochondrial Membranes (drug effects, metabolism)
  • Pancreatic Neoplasms (genetics, metabolism, pathology)
  • Permeability
  • Phenanthrenes (pharmacology)
  • RNA Interference
  • Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, genetics, metabolism)
  • Signal Transduction (drug effects)
  • TNF-Related Apoptosis-Inducing Ligand (pharmacology)
  • Transfection
  • bcl-2-Associated X Protein (metabolism)

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