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Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells.

Abstract
Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As(2)O(3)) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As(2)O(3) is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As(2)O(3) efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROS-inducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As(2)O(3)-mediated apoptosis in As(2)O(3)-resistant HL-60 cells. While 1 microM As(2)O(3) or 25 microM DHA reduced cell viability to 85.8% +/- 2.9% and 69.2% +/- 3.6%, combined treatment with As(2)O(3) and DHA reduced viability to 13.0% +/- 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2-associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As(2)O(3) and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As(2)O(3) and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As(2)O(3) and suggest that the combination of As(2)O(3) and DHA could be more broadly applied in leukemia therapy.
AuthorsSanda Sturlan, Melanie Baumgartner, Erich Roth, Thomas Bachleitner-Hofmann
JournalBlood (Blood) Vol. 101 Issue 12 Pg. 4990-7 (Jun 15 2003) ISSN: 0006-4971 [Print] United States
PMID12609832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Antioxidants
  • Arsenicals
  • BAX protein, human
  • Oxides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • Vitamin E
  • Docosahexaenoic Acids
  • Oleic Acid
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • arsenic trioxide
Topics
  • Antineoplastic Agents (administration & dosage, pharmacology)
  • Antioxidants (pharmacology)
  • Apoptosis (drug effects)
  • Arsenicals (administration & dosage, pharmacology)
  • Caspase 3
  • Caspases (metabolism)
  • Docosahexaenoic Acids (administration & dosage, pharmacology)
  • Drug Interactions
  • Drug Resistance, Neoplasm
  • HL-60 Cells (drug effects, pathology)
  • Humans
  • Leukemia (drug therapy, pathology)
  • Lipid Peroxidation (drug effects)
  • Membrane Potentials (drug effects)
  • Mitochondria (ultrastructure)
  • Oleic Acid (pharmacology)
  • Oxides (administration & dosage, pharmacology)
  • Proto-Oncogene Proteins (analysis)
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species (metabolism)
  • Tumor Cells, Cultured
  • Vitamin E (pharmacology)
  • bcl-2-Associated X Protein

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