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

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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.

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Acknowledgement

We thank Mr. Piyadon Sathavorasmith and Ms. Suttinee Phuagkhaopong for technical assistance. We thank Ms. Nanapas Bhagaman, a biostatistician at the Department of Epidemiology, Faculty of Public Health, Mahidol University for advice on statistic. This work was supported by research grant from Mahidol University to PP and KC. WT was supported by the Department of Medical Services, Ministry of Public Health, Thailand (Grant Number 59-59-407308).

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand

    Pannaree Piromkraipak, Supeenun Unchern, Porntip Supavilai & Pornpun Vivithanaporn

  2. Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand

    Kant Sangpairoj & Kulathida Chaithirayanon

  3. Division of Anatomy, Department of Preclinical Science, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand

    Kant Sangpairoj

  4. Prasat Neurological Institute, Bangkok, Thailand

    Wuttipong Tirakotai

  5. Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Christopher Power

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  1. Pannaree Piromkraipak
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Correspondence to Pornpun Vivithanaporn.

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10571_2017_507_MOESM1_ESM.eps

Supplementary Fig. 1 Cytotoxic effects of LTRAs on human glioblastoma cell. U373 cells were treated with montelukast (a) and zafirlukast (b). Cytotoxicity was measured by LDH assays at 24 h post-exposure. LTRAs, at concentrations higher than 10 μM, were toxic to glioblastoma cells. Data were expressed as median with interquartile range. Kruskal–Wallis H test was used for statistical analysis and statistical significance was donated as ** (p < 0.01). a: H = 19.63, p = 0.0015. b: H = 17.82, p = 0.0032. Supplementary material 1 (EPS 1313 kb)

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Piromkraipak, P., Sangpairoj, K., Tirakotai, W. et al. Cysteinyl Leukotriene Receptor Antagonists Inhibit Migration, Invasion, and Expression of MMP-2/9 in Human Glioblastoma. Cell Mol Neurobiol 38, 559–573 (2018). https://doi.org/10.1007/s10571-017-0507-z

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