MK886-induced apoptosis depends on the 5-LO expression level in human malignant glioma cells

J Neurooncol. 2010 May;97(3):339-46. doi: 10.1007/s11060-009-0036-9. Epub 2009 Oct 28.

Abstract

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products may play a key role in the development and progression of human cancers. In this study, we analyzed the effects of a 5-LO inhibitor, which inhibits the conversion of arachidonic acid to leukotrienes, on cell proliferation and apoptosis in human malignant glioma cells, including 5-LO-expressing cells U-87MG, A172 and 5-LO non-expressing cell U373. Growth of U-87MG and A172 cells, but not that of U373 cells, was inhibited in a dose-dependent manner by treatment with MK886. Similarly, specific 5-LO silencing by small interfering RNA reduced the growth of U-87MG and A172 cells. MK886 treatment reduced 5-LO activity independently of 5-LO-activating protein (FLAP) in human malignant glioma cells. MK886 treatment also induced cell apoptosis, measured by DNA fragmentation and nuclear condensation, in U-87MG and A172 cells but there were no signs in U373 cells. Moreover, this treatment reduced ERKs phosphorylation and anti-apoptotic molecule Bcl-2 expression, and increased Bax expression in U-87MG and A172 cells. In summary, our results show there is a link between the 5-LO expression status and the extent of MK886-inhibited cell proliferation and apoptosis. Taken together, this study suggest that 5-LO is a possible target for treating patients with gliomas, and 5-LO inhibition might be potent therapy for patients with 5-LO-expressing malignant gliomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects
  • Dose-Response Relationship, Drug
  • Flow Cytometry / methods
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioma / pathology*
  • Humans
  • Indoles / pharmacology*
  • Lipoxygenase Inhibitors / pharmacology*
  • Mutation / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Time Factors
  • Transfection / methods
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Apoptosis Regulatory Proteins
  • Indoles
  • Lipoxygenase Inhibitors
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • MK-886
  • Arachidonate 5-Lipoxygenase