Cysteinyl leukotriene receptor antagonists induce apoptosis and inhibit proliferation of human glioblastoma cells by downregulating B-cell lymphoma 2 and inducing cell cycle arrest

Abstract

Glioblastoma is the most aggressive type of brain cancer with the highest proliferation, invasion, and migration. Montelukast and zafirlukast, 2 widely used leukotriene receptor antagonists (LTRAs) for asthma treatment, inhibited invasion and migration of glioblastoma cell lines. Montelukast induces apoptosis and inhibits cell proliferation of various cancer cells. Herein, apoptotic and antiproliferative effects of montelukast and zafirlukast were investigated in 2 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 the therapeutic potential of LTRAs in glioblastoma.

Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells

“…Furthermore, leukotrienes have also been implicated in cancer cell growth, increased angiogenesis and metastasis [ 16 ]. Long-term zafirlukast treatment reduces cancer risks in cohorts of asthma patients [ 20 ] and CysLTR1 antagonists have been shown to control tumor growth and cell death in a variety of tumor entities [ 22 , 23 , 24 , 25 , 26 , 27 ]. In addition, zafirlukast has recently been repurposed as TNFR1 inhibitor, by interfering with ligand-independent and -dependent TNFR1 clustering [ 28 , 29 ].…”

“…CysLTR1 expression is associated with poor survival of colorectal [ 22 ] and prostate cancer [ 23 ]. Importantly, zafirlukast and other leukotriene receptor antagonists inhibit tumor growth, induce apoptosis or prevent the occurrence of carcinomas in vitro and in vivo, including glioblastoma [ 24 ], lung [ 25 ] and prostate cancer [ 23 ], colon carcinoma [ 22 , 26 ] and triple-negative breast cancer [ 27 ]. Recently, zafirlukast has also been repurposed as inhibitor of Tumor Necrosis Factor α (TNFα)-induced TNFR1 pre-ligand assembly domain (PLAD)-mediated TNFR1 activation [ 28 , 29 ].…”

Cysteinyl Leukotriene Pathway and Cancer

“…Montelukast and zafirlukast inhibited proliferation and induced apoptosis of glioblastoma cells (A172 and U-87 MG cells) in a concentration-dependent manner; both medications decreased Bcl-2 expression without affecting Bax level [ 79 ]. Montelukast induced more apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells; zafirlukast caused cell cycle arrest at G0/G1 phase by upregulating the expression of p53 and p21 and showed a greater antiproliferative effect than montelukast [ 79 ].…”

“…Montelukast and zafirlukast inhibited proliferation and induced apoptosis of glioblastoma cells (A172 and U-87 MG cells) in a concentration-dependent manner; both medications decreased Bcl-2 expression without affecting Bax level [ 79 ]. Montelukast induced more apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells; zafirlukast caused cell cycle arrest at G0/G1 phase by upregulating the expression of p53 and p21 and showed a greater antiproliferative effect than montelukast [ 79 ]. Montelukast and zafirlukast, but not zileuton, significantly inhibited migration and invasion of glioblastoma cells, as well as inhibiting the expression and activities of MMP-2 and MMP-9 in glioblastoma cells and primary human astrocytes, suggesting the important role of CysLT 1 R in migration and invasion of glioblastoma [ 80 ].…”

“…Montelukast induced cell cycle arrest and apoptosis of neuroblastoma cells. Piromkraipak P, 2018 [ 79 ] glioblastoma cell lines (A172, U-87 MG) Montelukast and zafirlukast inhibited proliferation and induced apoptosis in a concentration-dependent manner in glioblastoma cells; both medications decreased Bcl-2 expression without affecting Bax level. Montelukast induced more apoptosis than zafirlukast in A172 cells, but not in U-87 MG cells; zafirlukast caused cell cycle arrest at G0/G1 phase by upregulating the expression of p53 and p21 and showed a greater antiproliferative effect than montelukast.…”