Akademik Veri Yönetim Sistemi
PHARMACEUTICALS, cilt.18, sa.4, ss.1-25, 2025 (SCI-Expanded)
Background: 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.
Objectives: 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 ETresistant
A549 (A549/90E) lung cancer cells. Methods: 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 apoptosisrelated
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. Results: Our results revealed that ES significantly
exerted cytotoxic effects on both wild-type and A549/90E cells compared with BEAS-2B
cells. The IC50 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 2xIC50 and ½ IC50 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 IC50
for ET and ½ IC50 for ES. ET ½ IC50, ES ½ IC50, and an ET ½ IC50 + ES ½ IC50 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
IC50 and ET ½ IC50 caused increased levels of caspase-3 (p < 0.01) and P-gP (p < 0.001), while
PTEN levels remained unchanged. The combination resulted in an increase in caspase-3
(p < 0.001) and PTEN (p < 0.001) amounts, alongside a decrease in P-gP (p < 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. Conclusions: 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.