The Anticancer Mechanism Of Antidepressant Drug Sertraline

Lung cancer is the leading cause of cancer-related mortality worldwide.Non-small cell lung cancer(NSCLC)comprises approximately 85% of lung cancers(NSCLC).In recent years,selective epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have become the standard treatment of advanced NSCLC.However,the primary and acquired resistance of NSCLC to EGFR-TKIs restricts the clinical efficacy of EGFR-TKIs.Therefore,developing drugs that can effectively overcome EGFR-TKIs tolerance is critical for the clinical treatment of NSCLC.In this study,we chose NSCLC as a disease indication and screened over 1,000 FDA-approved drugs by bioinformatics.Through this approach,we identified that sertraline,an antidepressant drug,had the potential to kill NSCLC and overcome NSCLC resistance.Therefore,we carried out systematical and biological verification in the present study.Our data showed that sertraline dose-dependently inhibited cell viability in a set of NSCLC cell lines with the half effective inhibitory concentration ranging from 5 to 10 μM.In addition,sertraline and erlotinib(a clinical EGFR-TKI)showed synergistic cytotoxicity.To understand the underlying mechanism of sertraline in the inhibition of cell growth,we further examined cell apoptosis and autophagy in treated cells.Our results showed that sertraline could not trigger obvious apoptotic cell death in EGFR TKI-resistant NSCLC cells.However,sertraline evidently induce autophagy in a concentration-dependent manner.Sertraline and sertraline/erlotinib inhibited p62 expression,and promoted marked autophagic flux in EGFR TKI-resistant NSCLC cells.Mechanistic studies further revealed that sertraline and the drug pair dose-dependently activated AMPK in resistant NSCLC cells,and suppressed mTOR and its downstream target protein S6 K.Blocade of AMPK either by pharmacological inhibitors or siRNA significantly reduced sertraline-or the drug pair-mediated cytotoxicity,suggesting that AMPK plays a critical role in their antitumor actions.To further investigate the efficacy of the combinatorial therapy in vivo,we further established an orthotopic lung tumor mouse model using EGFR TKI-resistant NSCLC cells(A549).Our data showed that compared to the vehicle or single agent alone,the comination of sertraline and erlotinib significantly inhibited the growth of malignant tumor and prolonged the survival of tumor-bearing mice.In summary,our study revealed the function and molecular mechanism of the antidepressant drug sertraline in the sensitization of erlotinib,providing a new perspective and therapeutic strategy for the treatment of EGFR TKI-resistant NSCLC.