montelukast and Lung-Neoplasms

Lung cancer is a major threat to public health and remains difficult to treat. Repositioning of existing drugs has emerged as a therapeutic strategy in lung cancer. Clinically, low-dose montelukast has been used to treat asthma.. We evaluated the potential of using montelukast to treat lung cancer.. Migration was detected using wound-healing and Transwell assays, the expression of CysLT1 using western blotting, and subcellular localization of CysLT1 using immunofluorescence. CRISPR/Cas9 technology was used to further investigate the function of CysLT1.. Subcellular localization staining showed that the CysLT1 distribution varied in murine and human lung cancer cell lines. Furthermore, montelukast suppressed CysLT1 expression in lung cancer cells. The treated cells also showed weaker migration ability compared with control cells. Knockout of CysLT1 using CRISPR/Cas9 editing in A549 cells further impaired the cell migration ability.. Montelukast inhibits the migration of lung cancer cells by suppressing CysLT1 expression, demonstrating the potential of using CysLT1 as a therapeutic target in lung cancer.

Topics: Acetates; Animals; Cell Movement; Humans; Leukotriene Antagonists; Lung Neoplasms; Mice

Pemetrexed (PEM) is an effective chemotherapeutic drug used for the treatment of clinical non-small-cell lung cancer (NSCLC) and is reported to induce severe hepatotoxicity. Exploring potential drugs which could counteract the side effects of PEM is of great clinical interest. Here, we aim to examine the beneficial effects of Montelukast, a novel anti-asthma drug, against PEM-induced cytotoxicity in hepatocytes, and to explore the underlying mechanism. We found that Montelukast reduces cytotoxicity of PEM in hepatocytes, confirmed by its increasing cell viability and reducing lactate dehydrogenase (LDH) release. In addition, Montelukast attenuated PEM-induced oxidative stress by reducing mitochondrial reactive oxygen species (ROS), increasing reduced glutathione (GSH), and downregulating NADPH oxidase 4 (NOX-4) expression. Importantly, Montelukast suppressed PEM-induced activation of the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and mitigated endoplasmic reticulum (ER) stress by reducing NLRP3, growth arrest, and DNA damage-inducible protein 34 (GADD34), CEBP-homologous protein (CHOP), and also blocking the eukaryotic initiation factor 2 (eIF-2α)/activating transcription factor 4 (ATF4) signaling pathway. Lastly, we found that Montelukast inhibited the transcriptional activity of nuclear factor kappa-B (NF-κB). Montelukast exerted a protective action against PEM-induced cytotoxicity in hepatocytes by mitigating ER stress and NLRP3 activation.

Topics: Acetates; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cyclopropanes; Endoplasmic Reticulum; Hepatocytes; Humans; Lung Neoplasms; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleotides; Oxidative Stress; Pemetrexed; Quinolines; Reactive Oxygen Species; Sulfides

Topics: Carcinoma, Non-Small-Cell Lung; Drug Repositioning; Humans; Lung Neoplasms; Molecular Docking Simulation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret

Tumor-derived exosomes can modulate the cancer microenvironment and induce metastatic spread. Exosomes may carry enzymes for leukotriene (LT) biosynthesis, but the role of exosomal LTs has not been studied in cancer. We isolated exosomes and malignant cells from pleura exudates from 14 patients with non-small cell lung cancer. Lipidomic profiles, migration and apoptosis were determined. Both exosomes and primary cancer cells contained γ-glutamyl transpeptidase 1 (GGT-1) and avidly transformed exogenous LTC

Topics: Acetates; Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Cyclopropanes; Exosomes; Female; Follow-Up Studies; Humans; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Lung Neoplasms; Male; Middle Aged; Pleural Neoplasms; Prognosis; Quinolines; Receptors, Leukotriene; Sulfides; Survival Rate; Tumor Cells, Cultured

Topics: Acetates; Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Biomarkers; Cell Death; Cell Line, Tumor; Cell Proliferation; Cyclopropanes; Disease Models, Animal; Humans; Leukotriene Antagonists; Lung Neoplasms; Models, Biological; Protein Transport; Quinolines; Signal Transduction; Sulfides; Tumor Burden; Xenograft Model Antitumor Assays