Abstract
To identify novel targets for the diagnosis, treatment and prognosis of cholangiocarcinoma, we screen ideal lead compounds and preclinical drug candidates with MYC inhibitory effect from the ZINC database, and verify the therapeutic effect of Dhea and 2-14,15-Eg on cholangiocarcinoma. The gene expression profiles of GSE132305, GSE89749, and GSE45001 were obtained respectively from the Gene Expression Omnibus database. The DEGs were identified by comparing the gene expression profiles of cholangiocarcinoma and normal tissues. GO, KEGG analysis and PPI network analyses were performed. LibDock, ADME and toxicity prediction, molecular docking and molecular dynamics simulations were used to identify potential inhibitors of MYC. Moreover, in vitro, MTT assay, colony-forming assay, the scratch assay and Western blotting were performed to verify the therapeutic effect of Dhea and 2-14,15-Eg. PPI network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study. A battery of computer-aided virtual techniques showed that Dhea and 2-14,15-Eg have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6, as well as could exist stably in natural circumstances. In vitro assays showed that Dhea and 2-14,15-Eg inhibited cholangiocarcinoma cellular viability, proliferation, and migration inhibiting expression of MYC. This study suggested that Dhea and 2-14,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application.
Highlights
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma which arises from the epithelial cells of bile ducts that often presents with locally advanced or metastatic disease and carries an extremely poor prognosis [1]
Protein-Protein Interaction (PPI) network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study
This study suggested that Dhea and 2–14,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application
Summary
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma which arises from the epithelial cells of bile ducts that often presents with locally advanced or metastatic disease and carries an extremely poor prognosis [1]. The current preferred treatment for CCA is surgical resection, but this method is only suitable for the early stage. For patients who in the middle and late stage do not suitable for operation, locoregional and chemoradiation treatments and targeted drug therapy are generally selected [3]. Even if comprehensive therapy is adopted, the therapeutic effect is not satisfactory. The 5-year overall survival for stages 3 and 4 CCA are 10 and 0%, respectively [4]. Cumulative number of CCA deaths have been increased by 39% because of increased disease incidence. Mortality rates are higher in men and boys (1.9 per 100 000) than in women and girls (1.5 per 100 000) [5]
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