Scopus İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/395
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Article Cytotoxic and Cytostatic Effects of Targeting mTOR and Hedgehog Pathways in Acute Myeloid Leukemia(Istanbul Univ, 2022-12-29) Cicek, Enes; Kucuktas, Fulya Mina; Yenigul, Munevver; Akcok, Emel Basak GencerObjectives: Acute myeloid leukemia (AML) is a highly aggressive heterogeneous hematopoietic malignancy characterized by a rapid and abnormal proliferation of immature myeloid leukemia cells in the bone marrow and peripheral blood. Aberrant alterations in signal transduction pathways are strongly associated with the progression of AML. This study aimed to investigate cell viability and the cell cycle in AML cells by targeting the Hedgehog and mTOR signaling pathways with rapamycin and GANT61. Materials and Method: The antiproliferative effect of rapamycin and GANT61 was assessed by the MTT cell viability assay in two AML cell lines: CMK and MOLM-13. The effect of the inhibitors on cell-cycle distribution was determined using propidium iodide staining and measured with flow cytometry. Results: Rapamycin, an mTOR inhibitor, and GANT61, a Gli-1 inhibitor, decreased the cell proliferation of CMK and MOLM-13 cells. The IC20 values, which is the drug concentration that inhibits cell growth by 20%, were combined and administered to the cells. The results show the drugs to have a combinatorial inhibitory effect on CMK cells but not on MOLM-13 cells. In addition, the combination of drugs arrested the cells during the G0/G1 phase. Conclusion: This study suggests a novel combination therapy approach for AML via mTOR and Hedgehog signaling pathway inhibition using rapamycin and GANT61, respectively. It also suggest further studies be performed to reveal the mechanism of action.Article Apatinib Sensitizes Human Breast Cancer Cells Against Navitoclax and Venetoclax Despite Up-Regulated Bcl-2 and Mcl-1 Gene Expressions(Kare Publ, 2021) Kavakcioglu Yardimci, Berna; Ozgun Acar, Ozden; Semiz, Asli; Sen, Alaattin; Acar, Ozden Ozgun; Yardımcı, Berna KavakcıoğluOBJECTIVE Defects in apoptotic cell death which restrict the success of conventional cytotoxic therapies have pivotal roles in a number of pathological conditions including cancer. However, a novel drug class targeting pro-survival Bcl-2 protein family members has been developed with the understanding of the structures and interactions of Bcl-2 proteins. Within this new class, Bcl-2/Bcl-xL inhibitor Navitoclax and Bcl-2 specific inhibitor Venetoclax have been shown to demonstrate strong anticancer activities on several types of cancers. But their low affinity to other anti-apoptotic proteins limits their clinical usage. Here, we investigated the cytotoxic and apoptotic effects of Navitoclax/Venetoclax and their combinations with specific tyrosine kinase inhibitor Apatinib on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines. METHODS MTT assay was used for the evaluation of the inhibition of cancer cell proliferation. ELISA test and Quantitative real-time PCR assay was performed to determine the role of caspase-3, Bak, Bax, Bcl-2, Bcl-xL and Mcl-1 proteins in the inhibition of cell proliferation triggered by the tested agents. RESULTS We found that aggressive MDA-MB-231 cell line was more sensitive to all tested agents. Apatinib significantly enhanced Navitoclax/Venetoclax mediated inhibition of cell viability in both cancer cell lines despite up-regulation in the expression levels of Bcl-2 and Mcl-1 genes. We further demonstrated significant Bak/Bax and caspase-3 expression in less aggressive MCF-7 cells. CONCLUSION Our findings have impacts on Navitoclax/Venetoclax plus Apatinib based therapy for breast adenocarcinoma. On the other hand, further studies should be conducted to elucidate the mechanisms underlying synergistic effects of Navitoclax/Venetoclax plus Apatinib combinations.Article Citation - Scopus: 1Glucosylceramide Synthase is a Novel Biomarker of Midostaurin-Induced Cytotoxicity in Non-Mutant FLT3 Positive Acute Myeloid Leukemia Cells(Istanbul University Press, 2021-12-03) Şahin, Hande Nur; Adan, AysunObjective: Glucosylceramide (GC) synthesized by glucosylce-ramide synthase (GCS) favors cell survival and proliferation in many cancers. However, it’s role in Fms-like tyrosine kinase 3 (FLT3) non-mutant Acute Myeloid Leukemia (AML) pathogenesis is not clarified. Midostaurin, a multi-kinase inhibitor, clinically benefits FLT3-mutated AML, however, its clinical efficacy is under-estimat-ed in FLT3 non-mutant AML. This study aimed to investigate the efficacy of combination of midostaurin with GCS inhibitor in FLT3 AML cell carrying wild-type FLT3 and the underlying molecular mechanisms. Material and Method: Cytotoxic and cytostatic effects of mido-staurin, PDMP (GCS inhibitor) alone and in combination on THP1 cells were determined by MTT assay and flow cytometric propidi-um iodide (PI) staining, respectively. Calcusyn software was used to calculate combination indexes (CIs). GCS expression was checked by western blot. Results: Midostaurin downregulated GCS. Simultaneous inhibition of FLT3 and GCS resulted in suppression of cell proliferation as compared to untreated control. Combinations showed synergistic cytotoxic effects (CI<1). Co-treatments increased cell cycle population at G2/M phase. Conclusion: Inhibition of GCS enhances the efficacy of midostau-rin in FLT3 non-mutant AML, which could be a novel therapeutic approach to increase midostaurin’s limited usage in the clinic after detailed mechanistic studies. © 2023 Elsevier B.V., All rights reserved.