Cytotoxicity and reversal effect of sertraline, fluoxetine, and citalopram on MRP1- and MRP7-mediated MDR

Abstract

Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent years, researchers have focused on understanding the mechanisms of multidrug resistance (MDR) in cancer cells and have identified the overexpression of ATP-binding cassette (ABC) transporters, including ABCC1/MRP1 and ABCC10/MRP7, as a key factor in the development of MDR. In this study, we aimed to investigate whether three drugs (sertraline, fluoxetine, and citalopram) from the selective serotonin reuptake inhibitor (SSRI) family, commonly used as antidepressants, could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse MDR in cancer cells. Using a combination of in silico predictions and in vitro validations, we analyzed the interaction of MRP1 and MRP7 with the drugs and evaluated their ability to hinder cell resistance. We used computational tools to identify and analyze the binding site of these three molecules and determine their binding energy. Subsequently, we conducted experimental assays to assess cell viability when treated with various standard chemotherapies, both with and without the presence of SSRI inhibitors. Our results show that all three SSRI drugs exhibited inhibitory/reversal effects in the presence of chemotherapies on both MRP1-overexpressed cells and MRP7-overexpressed cells, suggesting that these medications have the potential to be repurposed to target MDR in cancer cells. These findings may open the door to using FDA-approved medications in combination therapy protocols to treat highly resistant malignancies and improve the efficacy of chemotherapy treatment. Our research highlights the importance of investigating and repurposing existing drugs to overcome MDR in cancer treatment.

Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy

“…Experimentally, they found that FLX reversed the MDR resistance of MRP1 overexpressing human epidermoid carcinoma cell line KB/CV60 to vincristine and doxorubicin. In parallel, the same sensitizing effect was observed for MRP7-overexpressing human ovarian adenocarcinoma cell line SKOV3/MRP7, which is resistant to paclitaxel [ 114 ]. Conclusively, FLX could be an efficient chemo-sensitizer for overcoming MDR.…”

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways

“…Fortunately, experimental evidence has suggested that a class of psychotropic medications known as selective serotonin reuptake inhibitors (SSRIs) exhibit anti-cancer properties. When combined with chemotherapy, SSRIs can effectively reverse drug resistance in cancer cells at safe and lower doses, thus highlighting their unique role as repurposed chemosensitizers [ 47 ]. SSRIs are antidepressant medications that are widely implemented in individuals suffering from depression, anxiety, autism, eating disorders, and nociceptive pain.…”