PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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Article Citation - WoS: 9Citation - Scopus: 11Inhibition of PI3K-AKT-mTOR Pathway and Modulation of Histone Deacetylase Enzymes Reduce the Growth of Acute Myeloid Leukemia Cells(Humana Press inc, 2023-12-26) Sansacar, Merve; Sagir, Helin; Akcok, Emel Basak Gencer; Gencer Akçok, Emel BaşakOne of the most widespread forms of blood cancer is known as acute myeloid leukemia (AML) which has an incidence of 80% with poor prognosis. Although there are different treatment methods for AML in clinic, the heterogeneity and complexity of the disease show that new treatments are needed. The aim of this study is to investigate the anticancer effects of inhibition of PI3K and HDAC enzymes on CMK and MOLM-13 AML cells lines. We demonstrated that the combination of LY294002 with SAHA and Tubastatin A significantly decreased the cell viability of both cell lines. In contrast, the LY294002 and PCI-34051 combination did not show a significant difference compared to the single LY294002 administration. The combination treatment of LY294002 and HDAC inhibitors did not induce apoptosis significantly. However, LY294002 + SAHA and LY294002 + PCI-34051 resulted in G0/G1 and G2/M cell cycle arrest in CMK cells, respectively. On the other hand, compared to control cells, LY294002 + SAHA and LY294002 + PCI-34051 led to G0/G1 phase arrest in MOLM-13. Furthermore, the LY294002 + PCI-34051 combination elevated the expression rate of LC3BII/I, an autophagy marker, in CMK cells by 2.5-fold. Our study revealed that the combinations of PI3K inhibitor and HDAC inhibitors showed a synergistic effect and caused a reduction in cell viability and increased cell cycle arrest on MOLM-13 and CMK cell lines. In addition, the expression of LC3BII was elevated in the CMK cell line. In conclusion, although more mechanistic studies are required, a combinational inhibition of PI3K and HDAC could be a promising approach for AML.Article Citation - WoS: 6Citation - Scopus: 8Histone Deacetylase Inhibition and Autophagy Modulation Induces a Synergistic Antiproliferative Effect and Cell Death in Cholangiocarcinoma Cells(Amer Chemical Soc, 2023-06-08) Yenigul, Munevver; Akcok, Emel Basak Gencer; Gencer Akçok, Emel BaşakCholangiocarcinoma, also known as biliary tract cancer,is an aggressiveadenocarcinoma arising from epithelial cells lining the intra- andextrahepatic biliary system. The effects of autophagy modulators andhistone deacetylase (HDAC) inhibitors in cholangiocarcinoma are notfully known. It is essential to understand the molecular mechanismsand the effects of HDAC inhibitors in the context of cholangiocarcinoma.The antiproliferative effect of different HDAC inhibitors and autophagymodulation was investigated by the MTT cell viability assay in TFK-1and EGI-1 cholangiocarcinoma cell lines. Combination indexes werecalculated using CompuSyn software. Consequently, apoptosis was detectedby Annexin V/PI staining. The effect of the drugs on the cell cyclewas measured by the propidium iodide staining. The HDAC inhibitionwas confirmed via acetylated histone protein levels by western blotting.HDAC inhibitors, MS-275 and romidepsin, showed a better synergisticeffect with the nocodazole combination. The combination treatmentexerted its growth inhibitory effect by cell cycle arrest and inductionof apoptosis. The cell cycle analysis of the combination treatmentshowed that the S phase and G2/M phase were achieved. Moreover, thenecrotic and apoptotic cell population increased after single HDACinhibitors and combination treatment. The anti-cancer effect of HDACinhibitors is revealed by acetylation levels of histones. While acetylationlevels were increased in response to HDAC inhibitors and autophagymodulator combinations, the HDAC expression decreased. This studyhighlights the importance of the combination of HDAC inhibition andautophagy modulators and demonstrates a synergistic effect, whichcould be a promising therapy and novel treatment approach for cholangiocarcinoma.Article Citation - WoS: 3Citation - Scopus: 3Determination of Promising Inhibitors for N-SH2 Domain of SHP2 Tyrosine Phosphatase: An in Silico Study(Springer, 2024-05-13) Akcok, Emel Basak Gencer; Guner, Huseyin; Akcok, Ismail; Gencer Akçok, Emel BaşakThere are many genes that produce proteins related to diseases and these proteins can be targeted with drugs as a potential therapeutic approach. Recent advancement in drug discovery techniques have created new opportunities for treating variety of diseases by targeting disease-related proteins. Structure-based drug discovery is a faster and more cost-effective approach than traditional methods. SHP2 phosphatase, encoded by the PTPN11 gene, has been the focus of much attention due to its involvement in many types of diseases. The biological function of SHP2 is enabled mostly by protein-protein interaction through its SH2 domains. In this study, we report the identification of a potential small molecule inhibitor for the N-SH2 domain of SHP2 by structure-based drug discovery approach. We utilized molecular docking studies, followed by molecular dynamics simulations and MM/PBSA calculations, to analyze compounds retrieved from the Broad's Drug Repurposing Hub and ZINC15 databases. We selected 10 hit compounds with the best docking scores from the libraries and examined their binding properties in the N-SH2 domain. We found that compound CID 60838 (Irinotecan) was the most suitable compound with a binding free energy value of - 64.45 kcal/mol and significant interactions with the target residues in the domain.