Montelukast ameliorated pemetrexed-induced cytotoxicity in hepatocytes by mitigating endoplasmic reticulum (ER) stress and nucleotide oligomerization domain-like receptor protein 3 (NLRP3) activation

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.