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Increasing melanoma cell death using inhibitors of protein disulfide isomerases to abrogate survival responses to endoplasmic reticulum stress.

Abstract
Exploiting vulnerabilities in the intracellular signaling pathways of tumor cells is a key strategy for the development of new drugs. The activation of cellular stress responses mediated by the endoplasmic reticulum (ER) allows cancer cells to survive outside their normal environment. Many proteins that protect cells against ER stress are active as protein disulfide isomerases (PDI) and the aim of this study was to test the hypothesis that apoptosis in response to ER stress can be increased by inhibiting PDI activity. We show that the novel chemotherapeutic drugs fenretinide and velcade induce ER stress-mediated apoptosis in melanoma cells. Both stress response and apoptosis were enhanced by the PDI inhibitor bacitracin. Overexpression of the main cellular PDI, procollagen-proline, 2-oxoglutarate-4-dioxygenase beta subunit (P4HB), resulted in increased PDI activity and abrogated the apoptosis-enhancing effect of bacitracin. In contrast, overexpression of a mutant P4HB lacking PDI activity did not increase cellular PDI activity or block the effects of bacitracin. These results show that inhibition of PDI activity increases apoptosis in response to agents which induce ER stress and suggest that the development of potent, small-molecule PDI inhibitors has significant potential as a powerful tool for enhancing the efficacy of chemotherapy in melanoma.
AuthorsPenny E Lovat, Marco Corazzari, Jane L Armstrong, Shaun Martin, Vittoria Pagliarini, David Hill, Anna M Brown, Mauro Piacentini, Mark A Birch-Machin, Christopher P F Redfern
JournalCancer research (Cancer Res) Vol. 68 Issue 13 Pg. 5363-9 (Jul 01 2008) ISSN: 1538-7445 [Electronic] United States
PMID18593938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Boronic Acids
  • Enzyme Inhibitors
  • Pyrazines
  • Bacitracin
  • Fenretinide
  • Bortezomib
  • Protein Disulfide-Isomerases
Topics
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Bacitracin (administration & dosage, pharmacology)
  • Boronic Acids (administration & dosage, pharmacology)
  • Bortezomib
  • Cell Death (drug effects)
  • Cell Survival (drug effects)
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Endoplasmic Reticulum (drug effects, metabolism, pathology)
  • Enzyme Inhibitors (administration & dosage, pharmacology)
  • Fenretinide (administration & dosage, pharmacology)
  • Humans
  • Melanoma (drug therapy, pathology)
  • Oxidative Stress (drug effects, physiology)
  • Protein Disulfide-Isomerases (antagonists & inhibitors)
  • Pyrazines (administration & dosage, pharmacology)
  • Treatment Outcome
  • Tumor Cells, Cultured

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