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Öğe An investigation on the effects of SIRT5 modulators on SIRT5 and cytochrome C protein expressions in K562 chronic myeloid leukemia cell line(University of Ankara, 2022) Özkan, Tülin; Koç, Aslı; Karabay, Arzu Zeynep; Hekmatshoar, Yalda; Sunguroğlu, AsumanObjective: SIRT5 is a mitochondrial protein that removes acetyl, malonyl and succinyl groups from lysine moieties in target proteins and interacts with cytochrome c and causes its deacetylation. There is no study on the effects of SIRT5 in K562 chronic myeloid leukemia cells. Resveratrol and Suramin are known to play a role in modulating the deacetylase and desuccinylase activities of SIRT5. It has been reported that Resveratrol induces apoptosis of K562 cells but effects of Suramin on the apoptosis of K562 cells are largely unknown. In this study, it was aimed to elucidate the effects of SIRT5 modulators Resveratrol and Suramin on proliferation and apoptosis of K562 cells and on SIRT5 and cytochrome c protein, a known target of SIRT5. Material and Method: K562 chronic myeloid leukemia cells were treated with increasing concentrations of suramin and resveratrol, cell proliferation was determined by MTT assay and BrdU incorporation. Apoptosis was determined with Annexin V staining by Flow cytometry. Western Blot analysis was performed to determine the effect of resveratrol and suramin on SIRT5 and Cytochrome c protein expression levels. Result and Discussion: Our results showed that suramin did not affect SIRT5 and cytochrome c protein expressions significantly and resveratrol decreased SIRT5 and increased cytochrome c expression. Suramin did not cause any changes on the apoptosis of K562 cells. Resveratrol decreased cell proliferation and induced apoptosis of K562 cells in accordance with the literature. The SIRT5-lowering effect of Resveratrol may have mediated its apoptotic effects.Öğe Downregulation of stearoyl-CoA desaturase 1 (SCD-1) promotes resistance to imatinib in chronic Myeloid Leukemia(2023) Altınok Güneş, Buket; Hekmatshoar, Yalda; Özkan, Tülin; Bozkurt, Süreyya; Erdoğan Aydos, O. Sena; Büyükaşık, Yahya; Aladağ, Elifcan; Sunguroğlu, AsumanChronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease resulting in the fusion of BCR and ABL genes and characterized by the presence of the reciprocal translocation t(9;22)(q34;q11). BCR-ABL, a product of the BCR-ABL fusion gene, is a structurally active tyrosine kinase and plays an important role in CML disease pathogenesis. Imatinib mesylate (IMA) is a strong and selective BCR-ABL tyrosine kinase inhibitor. Although IMA therapy is an effective treatment, patients may develop resistance to IMA therapy over time. This study investigated the possible genetic resistance mechanisms in patients developing resistance to IMA. We did DNA sequencing in order to detect BCR-ABL mutations, which are responsible for IMA resistance. Moreover, we analyzed the mRNA expression levels of genes responsible for apoptosis, such as BCL-2, P53, and other genes (SCD-1, PTEN). In a group of CML patients resistant to IMA, when compared with IMA-sensitive CML patients, a decrease in SCD-1 gene expression levels and an increase in BCL-2 gene expression levels was observed. In this case, the SCD-1 gene was thought to act as a tumor suppressor. The present study aimed to investigate the mechanisms involved in IMA resistance in CML patients and determine new targets that can be beneficial in choosing the effective treatment. Finally, the study suggests that the SCD-1 and BCL-2 genes may be mechanisms responsible for resistance.Öğe Evidence for health-promoting properties of Lepidium Sativum L.: an updated comprehensive review(2022) Hekmatshoar, Yalda; Özkan, Tülin; Saadat, Yalda RahbarLepidium sativum L. is a common herb distributed worldwide, used as a food ingredient and therapeutic agent in traditional medicine for treating health-related disorders. L. sativum and its extracts have been described to possess numerous biological activities including antimicrobial, antidiabetic, antioxidant, antidiarrheal, anticancer, and numerous health-promoting effects in in vivo and in vitro studies. The purpose of this review is to summarize the findings describing important biological functions and therapeutic effects of L. sativum in various cell lines and animal models. In this review, the English-language articles were gathered from electronic databases including Web of Science, PubMed and Google Scholar with no time limit applied to any database. The search terms used in this review include, "Lepidium sativum L." and/or "chemical composition", "health benefits", "antimicrobial", "antioxidant", "anticancer", "diuretic", "nephro-protection", "antidiarrheal", "antidiabetic", "anti-asthmatic", "neuroprotection", "metabolic", "bone fracture", and "reproductive performance". Additional and eligible studies were collected from reference lists of appropriate articles. The information presented will be helpful to attract more interest toward medicinal plants by defining and developing novel clinical applications and new drug formulations in the future. Pre-clinical studies showed that L. sativum possesses potent health-promoting effects involving various molecular mechanisms. Taken all together, data suggested that identified herbal plants such as L. sativum, can be exploited as nutritional and therapeutic agents to combat various ailments. Despite much research in this field, further comprehensive in vitro/in vivo studies and clinical trials are needed to identify the mechanisms underlying the biological and therapeutic activities of L. sativum.Öğe Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a bioinformatics study(2023) Hekmatshoar, Yalda; Saadat, Yalda Rahbar; Özkan, Tülin; Bozkurt, Süreyya; Gürel, Aynur KaradağImatinib (IMA) and nilotinib are the first and second generations of BCR-ABL tyrosine kinase inhibitors, which widely applied in chronic myeloid leukemia (CML) treatment. Here we aimed to provide new targets for CML treatment by transcriptome analysis. Microarray data GSE19567 was downloaded and analyzed from Gene Expression Omnibus (GEO) to identify common genes, which are downregulated or upregulated in K562-imatinib and K562-nilotinib treated cells. The differentially expressed genes (DEGs) were assessed, and STRING and Cytoscape were used to create the protein-protein interaction (PPI) network. In imatinib and nilotinib treated groups' comparison, there were common 626 upregulated and 268 downregulated genes, which were differentially expressed. The GO analysis represented the enrichment of DEGs in iron ion binding, protein tyrosine kinase activity, transcription factor activity, ATP binding, sequence-specific DNA binding, cytokine activity, the mitochondrion, sequence-specific DNA binding, plasma membrane and cell-cell adherens junction. KEGG pathway analysis revealed that downregulated DEGs were associated with pathways including microRNAs in cancer and PI3K-Akt signaling pathway. Furthermore, upregulated DEGs were involved in hematopoietic cell lineage, lysosome and chemical carcinogenesis. Among the upregulated genes, MYH9, MYH14, MYL10, MYL7, MYL5, RXRA, CYP1A1, FECH, AKR1C3, ALAD, CAT, CITED2, CPT1A, CYP3A5, CYP3A7, FABP1, HBD, HMBS and PPOX genes were found as hub genes. Moreover, 20 downregulated genes, YARS, AARS, SARS, GARS, CARS, IARS, RRP79, CEBPB, RRP12, UTP14A, PNO1, CCND1, DDX10, MYC, WDR43, CEBPG, DDIT3, VEGFA, PIM1 and TRIB3 were identified as hub genes. These genes have the potential to become target genes for diagnosis and therapy of CML patients.Öğe Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia(2024) Karabay, Arzu Zeynep; Özkan, Tülin; Gürel, Aynur Karadağ; Koç, Aslı; Hekmatshoar, Yalda; Sunguroğlu, Asuman; Aktan, Fügen; Büyükbingöl, ZelihaChemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.Öğe The Impact of Olaparib on Metabolic Pathways in Triple Negative Breast Cancer: A Bioinformatics Approach(2024) Hekmatshoar, YaldaAim: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer (BC) characterized by the lacking estrogen receptors, progesterone receptors, and HER2 expression, making it challenging to treat with targeted therapies. Olaparib, a PARP inhibitor, has shown promise in treating TNBC, particularly in patients with BRCA1 or BRCA2 mutations. This study aims to elucidate the metabolic pathways affected by olaparib in TNBC using bioinformatics analysis. Material and Method: For bioinformatics analysis, mRNA microarray data of control MDA-MB-468 cells (non-treated) and OlaR MDA-MB-468 (3μM olaparib-treated MDA-MB-468 cells) with the study numbered GSE165914 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to analyze and identify differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto gene and genome encyclopedia (KEGG) analysis were carried out for DEGs to determine significant genes and the biological pathways influenced by olaparib treatment. Protein-protein interaction (PPI) network analysis further identified key proteins and interactions within these pathways. Results: For GEO2R analysis adjusted P-value1.0 were selected. The results revealed the upregulation of 2277 genes and downregulation of 2298 genes in olaparib-treated cells compared to the controls. It was reported that DEGs enriched in pathways including, metabolic pathways, pathways in cancer, chemical carcinogenesis - reactive oxygen species, cell cycle, autophagy - animal, Efferocytosis and TNF signaling pathway. Both upregulated and downregulated DEGs were associated with metabolic pathways. Moreover, NDUFA5, NDUFA6, NDUFS6, NDUFB3, NDUFB10, NDUFB7, NDUFA7, NDUFA9, H2AC8, H2AC13, H2AC17, H4C11, H4C12, H2BC12, H2BC21 and H2BC4 were identified as the most significant candidate genes. Conclusion: This comprehensive bioinformatics approach provides insights into the molecular mechanisms of olaparib's action and identifies potential targets for combination therapies to enhance treatment efficacy in breast cancer.Öğe Methylsulfonylmethane induces caspase-dependent apoptosis in acute myeloid leukemia cell lines(2024) Hekmatshoar, Yalda; Karabay, Arzu Zeynep; Özkan, Tülin; Koç, Aslı; Sunguroğlu, AsumanBackground: Acute myeloid leukemia (AML) is a heterogeneous ailment in both biological and clinical concepts. Numerous efforts have been devoted to discover natural compounds for combating cancer, which showed great potential in cancer management. Methylsulfonylmethane (MSM), an organosulfur dietary supplement, is utilized for improving various clinical conditions, particularly osteoarthritis. MSM can exert antitumor activity in a wide range of cancers. Objectives: The molecular mechanisms of action underlying antileukemic activity of MSM remain unclear. In this regard, we aimed to investigate the anticancer properties of MSM on human AML cell lines (U937 and HL60) with focus on underlying cell death mechanism. Methods: Anticancer activity of the MSM was examined employing MTT assay, Annexin V-PE/7AAD staining, caspase3/7 activity test, and real-time qPCR. Both cell lines were treated with different concentrations (50-400 mM) of MSM for 24 h. Pretreatment of the cells with a caspase inhibitor (i.e., Z-VAD-fmk) was performed for the assessment of apoptosis induction. Results: The results of MTT assay revealed that in both cell lines, the MSM markedly reduced cell viability in comparison to the control cells. Additionally, findings of Annexin V-7AAD staining revealed that MSM induced apoptosis and activated caspase 3/7 in both cell lines markedly. Real-time quantitative PCR results also supported the induction of apoptosis in AML cells. MSM altered the expression levels of various apoptotic genes (BAX, BAD, and BIM). Conclusion: Overall, our results indicated that MSM could induce apoptosis in AML cell lines in a dose-dependent manner, which therefore could be utilized as an antileukemic agent.Öğe Mitochondria-specific targeting to overcome imatinib resistance in chronic myeloid leukemia cells(Elsevier, 2024) Hekmatshoar, Yalda; Özkan, Tülin; Karabay, Arzu Zeynep; Koç, Aslı; Gürel, A. Karadağ; Vignais, Marie-Luce; Sunguroğlu, A....Öğe Nilotinib exhibits less toxicity than imatinib and influences the immune state by modulating iNOS, p-p38 and p-JNK in LPS/IFN gamma-activated macrophages(2023) Karabay, Arzu Zeynep; Özkan, Tülin; Koç, Aslı; Hekmatshoar, Yalda; Gürkan-Alp, A. Selen; Sunguroğlu, AsumanIn this study, we aimed to analyze the effects of first and second-generation Bcr-Abl tyrosine kinase inhibitors, imatinib and nilotinib on LPS/IFN gamma activated RAW 264.7 macrophages. Our data revealed that imatinib was less effective on nitrite levels and more toxic on macrophages compared to nilotinib. Therefore, we further analysed the effect of nilotinib on various inflammatory markers including iNOS, COX-2, NFkB, IL-6, p-ERK, p-p38 and p-JNK in LPS/IFN gamma activated RAW264.7 macrophages. Spectrophotometric viability test and Griess assay,western blot, RT-PCR and luciferase reporter assays were used to analyze the biological activity of nilotinib. Our findings revealed that nilotinib decreases nitrite levels, iNOS mRNA, iNOS and p-p38 protein expressions significantly whereas induces IL-6 mRNA and p-JNK protein expressions at particular doses. We did not find significant effect of nilotinib on COX-2, p-ERK and nuclear p65 proteins and NFkB transcriptional activity. In addition, the binding mode of nilotinib to iNOS protein was predicted by molecular docking. According to the docking analyses, nilotinib exhibited hydrophobic interactions between MET349, ALA191, VAL346, PHE363, TYR367, MET368, CYS194, TRP366 residues at the binding pocket and the molecule as well as van der Waals interactions at specific residues. In conclusion, our results reveal that, in addition to its anticancer activity, nilotinib can exhibit immune modulatory effects on macrophages through its effects on iNOS, IL-6, p-p38 and p-JNK.Öğe Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line(2023) Hekmatshoar, Yalda; Karadağ Gürel, Aynur; Özkan, Tülin; Saadat, Yalda Rahbar; Koç, Aslı; Karabay, Arzu Zeynep; Bozkurt, Süreyya; Sunguroğlu, AsumanPurpose: Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of BCR-ABL protein. Imatinib (IMA) is considered as the first line therapy in management of CML which particularly targets the BCR-ABL tyrosine kinase protein. However, emergence of resistance to IMA hinders its clinical efficiency. Hence, identifying novel targets for therapeutic approaches in CML treatment is of great importance. Here, we characterize a new subpopulation of highly adherent IMA-resistant CML cells that express stemness and adhesion markers compared to naive counterparts. Materials and methods: We performed several experimental assays including FISH, flow cytometry, and gene expression assays. Additionally, bioinformatics analysis was performed by normalized web-available microarray data (GSE120932) to revalidate and introduce probable biomarkers. Protein-protein interactions (PPI) network was analyzed by the STRING database employing Cytoscape v3.8.2. Results: Our findings demonstrated that constant exposure to 5 μM IMA led to development of the adherent phenotype (K562R-adh). FISH and BCR-ABL expression analysis indicated that K562R-adh cells were derived from the original cells (K562R). In order to determine the role of various genes involved in epithelial-mesenchymal transition (EMT) and stem cell characterization, up/down-regulation of various genes including cancer stem cell (CSC), adhesion and cell surface markers and integrins were observed which was similar to the findings of the GSE120932 dataset. Conclusion: Treating CML patients with tyrosine kinase inhibitors (TKIs) as well as targeting adhesion molecules deemed to be effective approaches in prevention of IMA resistance emergence which in turn may provide promising effects in the clinical management of CML patients.Öğe Some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives overcome imatinib resistance by induction of apoptosis and reduction of P-glycoprotein activity(2023) Hekmatshoar, Yalda; Özkan, Tülin; Alp, Mehmet; Gürkan-Alp, A. Selen; Sunguroğlu, AsumanImatinib (IMA) is a tyrosine kinase inhibitor (TKI) introduced for the chronic myeloid leukemia (CML) therapy. Emergence of IMA resistance leads to the relapse and failure in CML therapy. Benzimidazole is a heterocyclic organic compound which is widely investigated for the development of anticancer drugs. In this study, we aimed to explore the anticancer effects of some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives on K562S (IMA-sensitive) and K562R (IMA-resistant) cells. To analyze the cytotoxic and apoptotic effects of the compounds, K562S, K562R, and L929 cells were exposed to increasing concentrations of the derivatives. Cytotoxic effects of compounds on cell viability were analyzed with MTT assay. Apoptosis induction, caspase3/7 activity were investigated with flow cytometry and BAX, BIM, and BAD genes expression levels were analyzed with qRT-PCR. Rhodamine123 (Rho-123) staining assays were carried out to evaluate the effect of compounds on P-glycoprotein (P-gp) activity. The hit compounds were screened using molecular docking, and the binding preference of each compounds to BCR-ABL protein was evaluated. Our results indicated that compounds triggered cytotoxicity, caspase3/7 activation in K562S and K562R cells. Rho-123 staining showed that compounds inhibited P-gp activity in K562R cells. Overall, our results reveal some benzimidazole derivatives as potential anticancer agents to overcome IMA resistance in CML.
