Erkisa, Merve2024-02-092024-02-092019-09Akgün, O. ve Arı, F. (2019). ''Effective and new potent drug combination: Histone deacetylase and wnt/beta-catenin pathway inhibitors in lung carcinoma cells''. Journal of Cellular Biochemistry, 120(9), 15467-15482.0730-23121097-4644https://doi.org/10.1002/jcb.28813https://onlinelibrary.wiley.com/doi/10.1002/jcb.28813https://hdl.handle.net/11452/39606Lung cancer is the most commonly diagnosed cancer worldwide with a high mortality rate. In this study, the therapeutic effect of combination valproic acid and niclosamide was investigated on human lung cancer cell line. The effects of the compounds alone and combination therapy on cell viability were determined by sulforhodamine B and adenosine 5 '-triphosphate viability assays. Flow cytometry was used to determine the cell death mechanism and DNA damage levels responsible for the cytotoxic effects of combination therapy. The presence of apoptosis in cells was supported by fluorescence microscopy and also by using inhibitors of the apoptotic signaling pathway. The increase in cellular reactive oxygen species (ROS) level in combination therapy was determined by H2DCFDA staining. The effect of N-acetyl-l-cysteine combination on ROS increase was investigated on cell viability. In addition, the expression levels of the proteins associated with epigenetic regulation and cell death were analyzed by Western blotting and gene expression levels were determined using real-time quantitative polymerase chain reaction.It was observed that the combination therapy showed a cytotoxic effect on the A549 lung cancer cells compared to the individual use of the inhibitors. The absence of this effect on normal lung cells revealed the presence of a selective toxic effect. When the mechanism of cytotoxicity is examined, it has been observed that combination therapy initiates the activation of tumor necrosis receptors and causes apoptosis by activated caspase. It was also observed that this extrinsic apoptotic pathway was activated on the mitochondrial pathway. In addition, ER stress and mitochondrial membrane potential loss associated with increased ROS levels induce cell death. When the data in this study were evaluated, combination therapy caused a dramatic decrease in cell viability by inducing the extrinsic apoptotic pathway in lung cancer cell line. Therefore, it was concluded that it can be used as an effective and new treatment option for lung cancer.eninfo:eu-repo/semantics/closedAccessBiochemistry & bolecular biologyCell biologyApoptosisLung cancerNiclosamideValproic acidEndoplasmic-reticulum stressValproic acidGrowth-inhibitionTargeted TherapyDown-regulationUp-regulationCancer cellsIn-vitroNiclosamideApoptosisA549 cellsAntineoplastic combined chemotherapy protocolsCell line, tumorCell proliferationCell survivalDNA damageDrug synergismEpigenesis, geneticHistone deacetylase inhibitorsHumansLung neoplasmsMembrane potentialMitochondrialNiclosamideReactive oxygen speciesValproic acidWnt signaling pathwayArticle0004768042001192-s2.0-850695241831546715482120931037769Biochemistry & molecular biologyCell biologyApoptosis; Pyrvinium Embonate; Cestode InfectionsAcetylcysteineAdenosine triphosphateCaspase 3Caspase 7Caspase 8Cytokeratin 18Histone deacetylaseHistone deacetylase 1Histone deacetylase 2Histone H3NiclosamideReactive oxygen metaboliteValproic acidAntineoplastic agentHistone deacetylase inhibitorNiclosamideReactive oxygen metaboliteValproic acidA-549 cell lineAntineoplastic activityApoptosisArticleBronchial cell lineCell densityCell viabilityCombination drug therapyControlled studyDNA damageDrug cytotoxicityDrug efficacyDrug potencyEndoplasmic reticulum stressFlow cytometryFluorescence microscopyGene expression levelHistone acetylationHumanHuman cellIc50Lung carcinomaMitochondrial membrane potentialPriority journalWnt signalingCell proliferationCell survivalDrug effectDrug potentiationGenetic epigenesisGeneticsLung tumorMetabolismTumor cell lineWnt signaling