Cytotoxic Effect of Escitalopram/Etoposide Combination on Etoposide-Resistant Lung Cancer
<b>Background:</b> Antidepressants are a class of pharmaceuticals utilized for the management of many psychiatric disorders, including depression. A considerable number of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), have been documented to demonstrate s...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/4/531 |
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| Summary: | <b>Background:</b> Antidepressants are a class of pharmaceuticals utilized for the management of many psychiatric disorders, including depression. A considerable number of antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), have been documented to demonstrate significant anticancer properties in various cancer cell lines. <b>Objectives:</b> The aim of this study was to evaluate the selective cytotoxic and apoptotic effects of escitalopram oxalate (ES) alone and in combination with etoposide (ET) on ET-resistant A549 (A549/90E) lung cancer cells. <b>Methods:</b> The cytotoxic effects of the drugs were determined by CCK-8, trypan blue, and neutral red assays. Apoptosis was observed by Annexin V fluorescein isothiocyanate (FITC)/PI and mitochondrial membrane potential (ΔΨm) assays. Moreover, the effects of the drugs, alone and in combination, on apoptosis-related proteins, caspase-3, PTEN, and resistance-related P-gP were determined by ELISA. The relationship between drugs and lung cancer was determined with protein–protein interaction (PPI) network analysis. <b>Results:</b> Our results revealed that ES significantly exerted cytotoxic effects on both wild-type and A549/90E cells compared with BEAS-2B cells. The IC<sub>50</sub> values of 48.67 and 51.6 μg/mL obtained for ET and ES, respectively, at the end of 24 h of incubation for A549 cells were applied reciprocally for each cell by including BEAS-2B together with the 2xIC<sub>50</sub> and ½ IC<sub>50</sub> values. The results of each combination were statistically evaluated with combination indices (CIs) obtained using the Compusyn synergistic effect analysis program. Combination doses with a synergistic effect in A549 and A549/90E cells and an antagonistic effect in BEAS-2B cells have been determined as ½ IC<sub>50</sub> for ET and ½ IC<sub>50</sub> for ES. ET ½ IC<sub>50</sub>, ES ½ IC<sub>50</sub>, and an ET ½ IC<sub>50</sub> + ES ½ IC<sub>50</sub> combination caused 18.37%, 55.19%, and 57.55% death in A549 cells, whereas they caused 44.9%, 22.4%, and 51.94% death in A549/90E cells, respectively. In A549 cells, the combination of ES ½ IC<sub>50</sub> and ET ½ IC<sub>50</sub> caused increased levels of caspase-3 (<i>p</i> < 0.01) and P-gP (<i>p</i> < 0.001), while PTEN levels remained unchanged. The combination resulted in an increase in caspase-3 (<i>p</i> < 0.001) and PTEN (<i>p</i> < 0.001) amounts, alongside a decrease in P-gP (<i>p</i> < 0.01) levels in A549/90E cells. The death mechanism induced by the combination was found to be apoptotic by Annexin V-FITC and ΔΨm assays. <b>Conclusions:</b> Based on our findings, ES was observed to induce cytotoxic and apoptotic activities in A549/90E cells in vitro. ES in combination therapy is considered to be effective to overcome ET resistance by reducing the amount of P-gP in A549/90E cells. |
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| ISSN: | 1424-8247 |