Şahin, Hande NurAdan, Aysun01. Abdullah Gül University04. Yaşam ve Doğa Bilimleri Fakültesi04.02. Moleküler Biyoloji ve Genetik2025-09-252025-09-2520220250-4685https://doi.org/10.1515/tjb-2021-0152/htmlhttps://hdl.handle.net/20.500.12573/2948Objectives: Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods: The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results: Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined anti-leukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions: Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies. © 2022 Elsevier B.V., All rights reserved.eninfo:eu-repo/semantics/closedAccessApoptosisFlt3 Wild Type AmlMidostaurinSphingosine KinaseSphingosine Kinase InhibitorCaspase 3Caspase 9Epidermal Growth Factor Receptor 2Lipocortin 5MidostaurinProtein Bcl 2Protein Kinase BProtein Tyrosine KinaseCaspase 3Caspase 9Cd135 AntigenEpidermal Growth Factor Receptor 2Lipocortin 5MidostaurinProgrammed Death 1 Ligand 1Protein Bcl 2Protein Kinase BProtein Tyrosine KinaseSphingosine Kinase 1TriacylglycerolAcute Myeloid LeukemiaApoptosisArticleCell Cycle AssayCell Cycle G0 PhaseCell Cycle ProgressionCell DeathCell ProliferationCell ViabilityCell Viability AssayControlled StudyCytotoxicityDrug PotentiationExocytosisFlow CytometryG1 Phase Cell Cycle CheckpointG2 Phase Cell Cycle CheckpointGene ExpressionGene OverexpressionHumanHuman CellIC50LipogenesisMts AssayMtt AssayMyelodysplastic SyndromeNecroptosisProtein ExpressionProtein PhosphorylationT Lymphocyte ActivationTHP-1 Cell LineTumor VolumeWestern BlottingArticle10.1515/tjb-2021-0152/html2-s2.0-85126294671