Sahin, Hande NurAdan, Aysun2025-09-252025-09-2520220250-46851303-829Xhttps://doi.org/10.1515/tjb-2021-0152https://search.trdizin.gov.tr/en/yayin/detay/1171764/combined-effect-of-midostaurin-and-sphingosine-kinase-1-inhibitor-on-fms-like-tyrosine-kinase-3-flt3-wild-type-acute-myeloid-leukemia-cellshttps://hdl.handle.net/20.500.12573/3477Sahin, Hande Nur/0000-0002-2382-3160; Adan, Aysun/0000-0002-3747-8580Objectives 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.eninfo:eu-repo/semantics/openAccessApoptosisFlt3 Wild Type AmlMidostaurinSphingosine KinaseSphingosine Kinase InhibitorApoptozFlt3 Yabanil Tip AmlMidostaurinSfingozin KinazSfingozin Kinaz InhibitoruArticle10.1515/tjb-2021-0152