Lipoxygenase inhibitors induce death receptor 5/TRAIL-R2 expression and sensitize malignant tumor cells to TRAIL-induced apoptosis

Cancer Sci. 2007 Sep;98(9):1417-23. doi: 10.1111/j.1349-7006.2007.00559.x. Epub 2007 Jul 23.


Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T-cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase-3, -8 and -10, and Bid. The underling mechanism by which NDGA enhanced TRAIL-induced apoptosis was examined. NDGA did not change the expression levels of anti-apoptotic factors, Bcl-x(L), Bcl-2, cIAP-1, XIAP and survivin. The expression of death receptor-related genes was investigated and it was found that NDGA specifically up-regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down-regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL-induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL-induced apoptosis. In contrast, NDGA neither enhanced TRAIL-induced apoptosis nor up-regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up-regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up-regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology
  • Benzoquinones / pharmacology
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Drug Synergism
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Jurkat Cells
  • Leukemia, T-Cell / enzymology
  • Leukemia, T-Cell / metabolism*
  • Leukemia, T-Cell / pathology*
  • Lipoxygenase Inhibitors / pharmacology*
  • Masoprocol / pharmacology
  • Mutant Chimeric Proteins / physiology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / physiology
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Apoptosis Regulatory Proteins
  • Benzoquinones
  • Immunoglobulin Fc Fragments
  • Lipoxygenase Inhibitors
  • Mutant Chimeric Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Masoprocol
  • 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone