Browsing by Author "Akcok, Emel Basak Gencer"

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Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study
(SPRINGER NATURE LINK, 2024) Akcok, Emel Basak Gencer; Guner, Huseyin; Akcok, Ismail; 0000-0002-6559-9144; 0000-0002-5444-3929; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Akcok, Emel Basak Gencer; Akcok, Ismail
There 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.
Histone Deacetylase Inhibition and Autophagy Modulation Induces a Synergistic Antiproliferative Effect and Cell Death in Cholangiocarcinoma Cells
(AMER CHEMICAL SOC, 2023) Yenigul, Munevver; Akcok, Emel Basak Gencer; 0000-0003-0468-721X; 0000-0002-6559-9144; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Yenigul, Munevver; Akcok Gencer, Emel Basak Emel Basak
Cholangiocarcinoma, 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.
Rapamycin and Niacin combination induces apoptosis and cell cycle arrest through autophagy activation on acute myeloid leukemia cells
(SPRINGER NATURE LINK, 2025) Subay, Lale Beril; Akcok, Emel Basak Gencer; Akcok, Ismail; 0000-0002-5444-3929; 0000-0002-6559-9144; 0009-0003-3594-4781; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Subay, Lale Beril; Akcok, Emel Basak Gencer; Akcok, Ismail
BackgroundAcute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by disorders in stem cell differentiation and excessive proliferation resulting in clonal expansion of dysfunctional cells called myeloid blasts. The combination of chemotherapeutic agents with natural product-based molecules is promising in the treatment of AML. In this study, we aim to investigate the anti-cancer effect of Rapamycin and Niacin combination on THP-1 and NB4 AML cell lines.Methods and ResultsThe anti-proliferative effects of Rapamycin and Niacin were determined by MTT cell viability assay in a dose- and time-dependent manner. The combination indexes were calculated by isobologram analysis. Furthermore, apoptosis was investigated by Annexin-V/Propidium Iodide(PI) double staining and cell cycle distribution was measured by PI staining. The expression levels of autophagy-related proteins were detected by western blotting. The combination of Rapamycin and Niacin synergistically decreased cell viability of AML cell lines. The combination treatment induced the apoptotic cell population of THP-1 and NB4 by 4.9-fold and 7.3-fold, respectively. In THP-1 cells, the cell cycle was arrested at the G2/M phase by 10% whereas the NB4 cells were accumulated at the G0/G1 phase. The combination treatment decreased Akt and p-Akt expression. Besides, the ATG7 expression was reduced by combination treatment on THP-1 cells. Similarly, the ATG5 level was downregulated in NB4 cells. The level of LC3B-II/LC3B-I, which is an indicator of autophagy flux, was upregulated in THP-1 and NB4 cells.ConclusionAlthough further studies are required, the combination of Rapamycin and Niacin combats cell proliferation by inducing cellular apoptosis, cell cycle arrest and autophagy activation.