Induction of apoptosis, cell proliferation, and cell cycle arrest by leukotriene receptor antagonists in triple negative breast cancer cells

[Speaker] Ruedeemars Yubolphan:1
[Co-author] Kran Suknuntha:1, Kanokpan Krueaprasertkul:1, Pornpun Vivithanaporn:1
1:Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand

Background: Breast cancer is the most frequently diagnosed malignancy in women. The triple-negative breast cancer (TNBC) subtype has the poorest prognosis and no specific therapy. The proinflammatory cysteinyl leukotrienes has been linked to tumorigenic processes in non-transformed epithelial cells by increasing proliferation, cell survival and migration. Overexpression of cysteinyl leukotriene receptor type 1 is associated with increased breast cancer cell migration and decreased survival of patients. Cysteinyl leukotriene receptor antagonists (LTRAs), such as montelukast and zafirlukast, are commonly used to treat allergies and asthma. A large epidemiological study reported that cysteinyl leukotriene antagonists decrease the risk of cancer development in asthma patients, especially lung, breast, colorectal, and liver cancers. The present study aimed to compare the direct effect of both drugs on cell viability, apoptosis, cell proliferation, and cell cycle in a triple-negative breast cancer MDA-MB-231 cells.
Method: Cell viability was determined by MTT assays. Apoptosis, cell proliferation and cell cycle were measured by flow cytometric analyses.
Results: Montelukast and zafirlukast diminished cell viability in a dose-dependent manner (5, 10, 20, and 50 µM). At 24 hours, 10 µM montelukast reduced cell viability to less than 40% while cells treated with 10 µM zafirlukast showed no change in cell viability. Cell viability was decreased to 50% by 20 µM zafirlukast. Consistently, flow cytometric analysis showed the elevation of Annexin V-FITC fluorescence intensity, a marker of apoptosis, in cells treated with 10 µM montelukast and 20 µM zafirlukast. Montelukast and zafirlukast at 20 µM increased the mean fluorescence intensity of CFSE staining, indicating that both drugs decrease cell proliferation. Interestingly, flow cytometric analysis of cell cycle with propidium iodide DNA staining showed that only 20 µM zafirlukast increase percentage of cells in the G0/G1 phase.
Conclusion: Montelukast is more cytotoxic to triple-negative breast cancer MDA-MB-231 cells than zafirlukast while zafirlukast is able to suppress cell proliferation by inducing G0/G1 cell-cycle arrest. Taken together, our findings suggest that the inhibition of cysteinyl leukotriene receptors might be a novel strategy for the intervention against hormone-independent breast cancer.

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