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Deciphering the mechanism of Indirubin and its derivatives in the inhibition of Imatinib resistance using a “drug target prediction-gene microarray analysis-protein network construction” strategy

Li, Huayao, Liu, Lijuan, Zhuang, Jing, Liu, Cun, Zhou, Chao, Yang, Jing, Gao, Chundi, Liu, Gongxi, Sun, Changgang
BMC complementary and alternative medicine 2019 v.19 no.1 pp. 75
DNA microarrays, alternative medicine, biomarkers, computer simulation, databases, drugs, gene expression, genes, mechanism of action, myeloid leukemia, patients, signal transduction, transcription factor NF-kappa B
BACKGROUND: The introduction of imatinib revolutionized the treatment of chronic myeloid leukaemia (CML), substantially extending patient survival. However, imatinib resistance is currently a clinical problem for CML. It is very importantto find a strategy to inhibit imatinib resistance. METHODS: (1) We Identified indirubin and its derivatives and predicted its putative targets; (2) We downloaded data of the gene chip GSE2810 from the Gene Expression Omnibus (GEO) database and performed GEO2R analysis to obtain differentially expressed genes (DEGs); and (3) we constructed a P-P network of putative targets and DEGs to explore the mechanisms of action and to verify the results of molecular docking. RESULT: We Identified a total of 42 small-molecule compounds, of which 15 affected 11 putative targets, indicating the potential to inhibit imatinib resistance; the results of molecular docking verified these results. Six biomarkers of imatinib resistance were characterised by analysing DEGs. CONCLUSION: The 15 small molecule compounds inhibited imatinib resistance through the cytokine-cytokine receptor signalling pathway, the JAK-stat pathway, and the NF-KB signalling pathway. Indirubin and its derivatives may be new drugsthat can combat imatinib resistance.