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

aggressive types of brain tumors. 5-lipoxygenase and cysteinylleukotriene receptor 1 (CysLT1) play a role inhuman carcinogenesis. Leukotriene receptor antagonists(LTRAs), anti-asthmatic drugs with mild side effects, haveanti-metastatic activity in epidermoid carcinoma, lungcarcinoma, and colon cancers as well as neuroprotectiveeffects. Herein, anti-migratory effects of two LTRAs,montelukast and zafirlukast, were investigated inglioblastoma cells. The level of CysLT1 in A172 cells wasincreased by 3.13 folds after IL-1b treatment. The mediantoxic concentration of LTRAs in A172, U373, and primaryastrocytes ranged from 7.17 to 26.28 lM at 24-h post-exposure.Both LTRAs inhibited migration and invasion ofglioma. Additionally, both drugs significantly inhibited theexpression and activities of MMP-2 and MMP-9 in A172and U373 glioblastoma cells and primary human astrocytes,suggesting that CysLT1 plays a role in migration andinvasion of glioma, and LTRAs are potential drugs toreduce migration and invasion.Keywords Montelukast Zafirlukast Gelatinase Migration Invasion Gliom

Cysteinyl Leukotriene Receptor Antagonists Induce Apoptosis and Inhibit Proliferation of Human Glioblastoma Cells by Down-regulating B-cell Lymphoma 2 and Inducing Cell Cycle Arrest

Glioblastoma is the most aggressive type of brain cancer with the highest proliferation, invasion and migration. Montelukast and zafirlukast, two widely used leukotriene receptor antagonists (LTRAs) for asthma treatment, inhibited invasion and migration of glioblastoma cell lines. Montelukast induces apoptosis and inhibites cell proliferation of various cancer cells. Herein, apoptotic and antiproliferative effects of montelukast and zafirlukast were investigated in two glioblastoma cell lines, A172 and U-87 MG. Both LTRAs induced apoptosis and inhibited cell proliferation of glioblastoma cells in a concentration-dependent manner. Montelukast was more cytotoxic and induced higher levels of apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells. Both drugs decreased expression of B-cell lymphoma 2 (Bcl-2) protein without affecting Bcl-2-associated X (Bax) levels. LTRAs also reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In contrast, zafirlukast showed a greater antiproliferative effect than montelukast and induced G0/G1 cell cycle arrest by upregulating p53 and p21 expression. These results suggested that therapeutic potential of LTRAs in glioblastoma.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author