PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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Article Citation - WoS: 1Citation - Scopus: 1Concurrent Inhibition of FLT3 and Sphingosine Kinase-1 Triggers Synergistic Cytotoxicity in Midostaurin Resistant FLT3-ITD Positive Acute Myeloid Leukemia Cells via Blocking FLT3/TAT5A Signaling to Induce Apoptosis(Taylor & Francis Ltd, 2025-03-21) Tecik, Melisa; Adan, AysunThe FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations observed in acute myeloid leukemia (AML) which contributes to disease progression and unfavorable prognosis. Midostaurin, a small FLT3 inhibitor (FLT3I), is clinically approved. However, patients generally possess acquired resistance when midostaurin used alone. Shifting the balance in the sphingolipid rheostat toward anti-apoptotic sphingosine kinase-1 (SK-1) or glucosylceramide synthase (GCS) is related to therapy resistance in cancer, however, their role in midostaurin resistant FLT3-ITD positive AML has not been previously investigated. We generated midostaurin resistant MV4-11 and MOLM-13 cell lines which showed increased IC50 values compared to their sensitive partner cells. SK-1 is overexpressed in resistant cells while GCS remains unchanged. Subsequent pharmacological targeting of SK-1 in resistant cells decreased SK-1 protein level, inhibited cell proliferation and showed additive or synergistic effect on cell growth, as confirmed by the Chou-Talalay combination index, and induced G0/G1 arrest (PI staining by flow cytometry). Cotreatment (SKI-II plus midostaurin) triggered apoptosis via phosphatidylserine exposure (annexin V/PI double staining). Mechanistically, induction of the intrinsic pathway of apoptosis was confirmed as increased activating cleavages of caspase-3 and PARP and increased Bax/Bcl-2 ratios. Activating phosphorylations of FLT3 (at tyrosine residue 591) and STAT5A (at tyrosine residue 694) dramatically inhibited in resistant cells treated with the combination. In conclusion, midostaurin resistance could be reversed by dual SK-1 and FLT3 inhibition in midostaurin resistant AML cell lines, providing the first evidence of a novel treatment approach to re-sensitize FLT3-ITD positive AML.Article Citation - WoS: 1Analysis of the in Vitro Nanoparticle-Cell Interactions via a Smoothing-Splines Mixed-Effects Model(Taylor & Francis Ltd, 2015-05-12) Dogruoz, Elifnur; Dayanik, Savas; Budak, Gurer; Sabuncuoglu, IhsanA mixed-effects statistical model has been developed to understand the nanoparticle (NP)-cell interactions and predict the rate of cellular uptake of NPs. NP-cell interactions are crucial for targeted drug delivery systems, cell-level diagnosis, and cancer treatment. The cellular uptake of NPs depends on the size, charge, chemical structure, and concentration of NPs, and the incubation time. The vast number of combinations of these variable values disallows a comprehensive experimental study of NP-cell interactions. A mathematical model can, however, generalize the findings from a limited number of carefully designed experiments and can be used for the simulation of NP uptake rates, to design, plan, and compare alternative treatment options. We propose a mathematical model based on the data obtained from in vitro interactions of NP-healthy cells, through experiments conducted at the Nanomedicine and Advanced Technologies Research Center in Turkey. The proposed model predicts the cellular uptake rate of silica, polymethyl methacrylate, and polylactic acid NPs, given the incubation time, size, charge and concentration of NPs. This study implements the mixed-model methodology in the field of nanomedicine for the first time, and is the first mathematical model that predicts the rate of cellular uptake of NPs based on sound statistical principles. Our model provides a cost-effective tool for researchers developing targeted drug delivery systems.