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1.
Artículo en Inglés | MEDLINE | ID: mdl-38117080

RESUMEN

Imatinib (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.


Asunto(s)
Biología Computacional , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas , Humanos , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Biología Computacional/métodos , Pirimidinas/farmacología , Mapas de Interacción de Proteínas , Perfilación de la Expresión Génica , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Células K562 , Redes Reguladoras de Genes/efectos de los fármacos
2.
Turk J Biol ; 47(4): 276-289, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38152617

RESUMEN

Background/aim: Photodynamic therapy (PDT) has received great attention over the past decade in the treatment of diseases such as leukemia which is a cancer of the blood and bone marrow cells that causes a significant number of deaths worldwide. In this study, it was aimed to investigate the effects of Nile blue-mediated PDT (NB-mediated PDT) on HL60 cells. Materials and methods: The effect of NB-mediated PDT on cell proliferation was evaluated with cell volume analysis using flow cytometry at 24 h. Cell apoptosis, ROS production, mitochondrial membrane potential, and cell cycle analysis were evaluated using annexin V-FITC, H2DCFDA, JC-1, and PI staining, respectively, by flow cytometry and fluorescence microscopy. The morphological and ultrastructural analyses were examined by Giemsa staining and SEM. CD11b staining is used to determine the differentiation of leukemia cells. Results: NB-mediated PDT induced an apoptotic response at 12.5 µM in HL60 cells. When Giemsa staining and SEM images were evaluated, apoptotic bodies, holes, and occasional folds were detected on the surfaces of cells in the NB-mediated PDT group. Conclusion: The NB-mediated PDT had no effect on the differentiation of leukemia cells, but this therapy affects the growth of HL60 cells in vitro, which may provide a new idea for removing leukemic cells from bone marrow intended for autologous transplant.

3.
Adv Med Sci ; 68(2): 238-248, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37421850

RESUMEN

PURPOSE: 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 â€‹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.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos/genética , Células K562 , Apoptosis , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Proteínas de Fusión bcr-abl/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Fenotipo
4.
Bioimpacts ; 12(2): 89-105, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35411297

RESUMEN

Introduction: Pompe disease (PD) is a disease caused by pathogenic variations in the GAA gene known as glycogen storage disease type II, characterized by heart hypertrophy, respiratory failure, and muscle hypotonia, leading to premature death if not treated early. The only treatment option, enzyme replacement therapy (ERT), significantly improves the prognosis for some patients while failing to help others. In this study, the determination of key genes involved in the response to ERT and potential molecular mechanisms were investigated. Methods: Gene Expression Omnibus (GEO) data, accession number GSE38680, containing samples of biceps and quadriceps muscles was used. Expression array data were analyzed using BRB-Array Tools. Biceps group patients did not receive ERT, while quadriceps received treatment with rhGAA at 0, 12, and 52 weeks. Differentially expressed genes (DEGs) were deeply analyzed by DAVID, GO, KEGG and STRING online analyses, respectively. Results: A total of 1727 genes in the biceps group and 1198 genes in the quadriceps group are expressed differently. It was observed that DEGs were enriched in the group that responded poorly to ERT in the 52nd week. Genes frequently changed in the weak response group; the expression of 530 genes increased and 1245 genes decreased compared to 0 and 12 weeks. The GO analysis demonstrated that the DEGs were mainly involved in vascular smooth muscle contraction, lysosomes, autophagy, regulation of actin cytoskeleton, inflammatory response, and the WNT signaling pathway. We also discovered that the WNT signaling pathway is highly correlated with DEGs. Several DEGs, such as WNT11, WNT5A, CTNNB1, M6PR, MYL12A, VCL, TLN, FYN, YES1, and BCL2, may be important in elucidating the mechanisms underlying poor response to ERT. Conclusion: Early diagnosis and treatment of PD are very important for the clinic of the disease. As a result, it suggests that the enriched genes and new pathways emerging as a result of the analysis may help identify the group that responds poorly to treatment and the outcome of the treatment. Obtained genes and pathways in neonatal screening will guide diagnosis and treatment.

5.
Leuk Res ; 102: 106523, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33607534

RESUMEN

INTRODUCTION: Chronic Myeloid Leukemia (CML) is a hematological disease which is characterized by the presence of BCR-ABL fusion protein. Imatinib (IMA), a tyrosine kinase inhibitor of BCR-ABL, is used as a frontline treatment.Although IMA aids in killing a majority of leukemia cells, it may not kill CML stem cells which are the primary roots of disease and therapy resistance. Recently, antimicrobial drugs have been gaining attention because of their selective targeting of cancer cells. Therefore, we now ask if combinational therapy of IMA with a targeted antimicrobial drug Azithromycin (AZT) can enhance the treatment efficiency in IMA resistant CML. METHODS: K562S (IMA sensitive) and K562R (IMA resistant) cells were treated with increasing concentrations of AZT to determine its effects on cell proliferation and apoptosis. Cell viability, apoptosis, caspase3/7 activity and P-glycoprotein (Pgp) function were investigated with spectrophotometric MTT assay and flow cytometric Annexin V staining, caspase 3/7 activity, and Rhodamine123 staining assays respectively. The expression levels of pro-apoptotic (BAX, BAD and BIM), anti- apoptotic (BCL-XL and BCL-2) and drug transporter (MDR-1 and MRP-1) genes were assessed with qRT-PCR. RESULTS: AZT treatment alone inhibited cell viability, induced apoptosis and enhanced caspase 3/7 activity in both K562S and high MDR-1 (Pgp) expressing K562R cells. Moreover, combination of AZT/IMA suppressed cell viability, induced apoptosis and caspase3/7 activity more effectively and significantly compared to K562R cells treated with only IMA or AZT. Furthermore, AZT and AZT/IMA combination decreased Pgp function in K562R cells in comparison with their controls. Based on qRT-PCR data, single AZT and combined AZT/IMA treatment also induced BAX/BCL-2 ratio significantly in both K562S and K562R cells. CONCLUSION: Single AZT and AZT/IMA combinational treatment can be proposed as a promising and effective treatment strategy for CML. One of the mechanisms underlying the potent anticancer effect of combined AZT/IMA could be its ability to inhibit Pgp function and increase intracellular accumulation of IMA which leads to the induction of apoptosis in K562R cells.


Asunto(s)
Antineoplásicos/farmacología , Azitromicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Mesilato de Imatinib/farmacología
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