montelukast and Triple-Negative-Breast-Neoplasms

Breast cancer is usually associated with metastatic features, poor prognosis, and high mortality. The epithelial-mesenchymal transition (EMT) process has been implicated in the initiation and metastasis of breast cancer.. The study aimed to investigate the possible role of montelukast (Mont), the cysteinyl leukotriene receptor (CystLT1R) antagonist, in mitigating EMT in triple-negative breast cancer (TNBC) (in vitro study) and solid Ehrlich carcinoma (SEC) bearing mice (in vivo study) as well as to clarify the underlying molecular mechanisms in the presence and absence of sirtuin-1 inhibitor (sirtinol; Sirt).. TNBC MDA-MB-231 cells were treated with either 5 μM Mont or 25 μM Sirt or both for 48 h. Alternatively, SEC cells were inoculated in mice to induce breast cancer. After 12 days, the mice were divided into four groups: Untreated SEC group (vehicle), Sirt group (1 mg/kg), Mont group (10 mg/kg), and cotreatment Sirt/Mont group. The mice groups received the assigned treatment for the consequent 16 days.. Mont and/or Sirt decreased cell proliferation, migration and suppressed EMT in both in vitro and in vivo experiments. All treatments downregulated sirtuin-1 and vimentin expression but upregulated E-cadherin expression. Furthermore, all treatments retarded angiogenesis as evidenced by decreased VEGF expression. These findings were associated with suppressing active protein kinase B (p-AKT).. Cotreatment with Sirt and Mont proved more effective anti-tumor activity in TNBC cell line and in SEC bearing mice than either treatment alone, which could be attributed to the inhibition of sirtuin-1 and AKT- activated pathways, with the subsequent inhibition of EMT.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Mice; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirtuin 1; Triple Negative Breast Neoplasms

Despite a discovery of hormonal pathways regulating breast cancer, a definitive cure for the disease requires further\ identification of alternative targets that provide a hormone-independent support. Apart from their role in inflammatory\ diseases, cysteinyl leukotriene (CysLT) receptor antagonists (LTRAs) decrease the risk of lung cancer in asthma patients\ and inhibit tumor progression in several malignancies. In the present study, we evaluate the effects of two chemically\ different, clinically relevant LTRAs (montelukast and zafirlukast) in a triple negative breast cancer cell line, MDAMB-\ 231. We found that these two LTRAs reduced breast cancer cell viability in a dose-dependent manner with the\ 50% inhibitory concentration (IC50) between 5-10 μM. Although both LTRAs have several pharmacological properties\ in common, we noticed that montelukast mainly induced apoptosis, while zafirlukast mainly exerted its action on cell\ cycle. However, the precise mechanisms responsible for such different effects remain unclear. In summary, our results\ suggest that CysLT plays a role in proliferation and survivability of breast cancer cells in the absence of hormonal stimuli.

Topics: Acetates; Apoptosis; Cell Cycle; Cell Proliferation; Cyclopropanes; Female; Humans; Indoles; Leukotriene Antagonists; Mitogens; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Sulfides; Sulfonamides; Tosyl Compounds; Triple Negative Breast Neoplasms; Tumor Cells, Cultured