Cysteinyl Leukotriene Receptor Antagonists Inhibit Migration, Invasion, and Expression of MMP-2/9 in Human Glioblastoma

Cell Mol Neurobiol. 2018 Mar;38(2):559-573. doi: 10.1007/s10571-017-0507-z. Epub 2017 Jun 9.

Abstract

Glioblastoma is one of the most malignant and aggressive types of brain tumors. 5-lipoxygenase and cysteinyl leukotriene receptor 1 (CysLT1) play a role in human carcinogenesis. Leukotriene receptor antagonists (LTRAs), anti-asthmatic drugs with mild side effects, have anti-metastatic activity in epidermoid carcinoma, lung carcinoma, and colon cancers as well as neuroprotective effects. Herein, anti-migratory effects of two LTRAs, montelukast and zafirlukast, were investigated in glioblastoma cells. The level of CysLT1 in A172 cells was increased by 3.13 folds after IL-1β treatment. The median toxic concentration of LTRAs in A172, U373, and primary astrocytes ranged from 7.17 to 26.28 μM at 24-h post-exposure. Both LTRAs inhibited migration and invasion of glioma. Additionally, both drugs significantly inhibited the expression and activities of MMP-2 and MMP-9 in A172 and U373 glioblastoma cells and primary human astrocytes, suggesting that CysLT1 plays a role in migration and invasion of glioma, and LTRAs are potential drugs to reduce migration and invasion.

Keywords: Gelatinase; Glioma; Invasion; Migration; Montelukast; Zafirlukast.

MeSH terms

  • Acetates / pharmacology
  • Acetates / therapeutic use
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / prevention & control
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Enzymologic
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Glioblastoma / prevention & control
  • Humans
  • Leukotriene Antagonists / pharmacology*
  • Leukotriene Antagonists / therapeutic use
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Matrix Metalloproteinase 9 / genetics
  • Neoplasm Invasiveness / genetics
  • Quinolines / pharmacology
  • Quinolines / therapeutic use
  • Receptors, Leukotriene / metabolism

Substances

  • Acetates
  • Leukotriene Antagonists
  • Quinolines
  • Receptors, Leukotriene
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • leukotriene D4 receptor
  • montelukast