Abstract
Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001). Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.
Highlights
Cancer is a leading cause of morbidity and mortality [1,2,3]
In our previous nationwide population-based cohort study, we found that cysteinyl leukotriene receptor antagonists (LTRAs) decreased cancer risk in a dose-dependent manner in asthma patients, and the significant chemo-preventing effect of LTRA was mainly observed in lung, breast, colorectal, and liver cancers [1]
Using a Water-Soluble Tetrazolium Salt-1 (WST-1) Cell Proliferation Assay, we found that 100 μM of montelukast induced more than 75% of growth inhibition in A549, H1299, H460, CL1-0, CL1-5, and Lewis lung carcinoma (LLC) (Figure 1a,b)
Summary
Much advancement has been made in lung cancer treatment, lung cancer remains the most common cause of cancer death [1,2,3]. Lung cancer is usually diagnosed in the advanced stages, and drug resistance develops sooner or later during the treatment course, leading to unsatisfying outcomes. Developing cancer-preventing strategies is as important as advancing anti-cancer strategies [1,2]. In our previous nationwide population-based cohort study, we found that cysteinyl leukotriene receptor antagonists (LTRAs) decreased cancer risk in a dose-dependent manner in asthma patients, and the significant chemo-preventing effect of LTRA was mainly observed in lung, breast, colorectal, and liver cancers [1]. The effect of montelukast on lung cancer has not been studied yet, and its underlying anti-cancer mechanisms have not been fully understood
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