Research Paper Volume 11, Issue 21 pp 9738—9766

Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats

Sheng Zhong 1, 2, 3, , Yang Bai 1, 4, , Bo Wu 4, 5, , Junliang Ge 4, , Shanshan Jiang 6, , Weihang Li 4, , Xinhui Wang 7, , Junan Ren 4, , Haiyang Xu 1, , Yong Chen 1, , Gang Zhao 1, ,

  • 1 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
  • 3 Department of Bioinformatics, Harvard Medical School, Boston, MA 02115, USA
  • 4 Clinical College, Jilin University, Changchun, China
  • 5 Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
  • 6 Institute of Zoology, China Academy of Science, Beijing, China
  • 7 Department of Oncology, The First Hospital of Jilin University, Changchun, China

received: July 30, 2019 ; accepted: October 28, 2019 ; published: November 9, 2019 ;

https://doi.org/10.18632/aging.102422
How to Cite

Copyright © 2019 Zhong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Glioblastoma is the most common type of malignant brain tumor. Bioinformatics technology and structure biology were effectively and systematically used to identify specific targets in malignant tumors and screen potential drugs.

Results: GBM patients have higher AURKA and KDR mRNA expression compared with normal samples. Then, we identified a small molecular compound, ENMD-2076, could effectively inhibit Aurora kinase A and VEGFR-2 (encoded by KDR) activities. ENMD-2076 is predicted without toxic properties and also has absorption and gratifying brain/blood barrier penetration ability. Further results demonstrated that ENMD-2076 could significantly inhibit GBM cell lines proliferation and vitality, it also suppressed GBM cells migration and invasion. ENMD-2076 induced glioblastoma cell cycle arrest in G2-M phase and apoptosis by inhibiting PI3K/AKT/mTOR signaling pathways. Additionally, ENMD-2076 prolonged the median survival time of tumor-bearing rats and restrained growth rate of tumor volume in vivo.

Conclusions: Our findings reveal that ENMD-2076 is a promising drug in dealing with glioblastoma and have a perspective application.

Methods: We show that AURKA and KDR genes are hub driver genes in glioblastoma with bioinformatics technology including WGCNA analysis, PPI network, GO, KEGG analysis and GSEA analysis. After identifying a compound via virtual screening analysis, further experiments were carried out to examine the anti-glioblastoma activities of the compound in vivo and in vitro.

Abbreviations

ADME: Absorption, distribution, metabolism, excretion; ADMET: Adsorption, distribution, metabolism, excretion, toxicity; AMES: Ames mutagenicity; ANOVA: Analysis of variance; AURKA: Aurora kinase A; AURKB: Aurora kinase B; BBB: Blood-brain barrier; BSA: Bovine serum albumin; CDC20: Cell division cycle 20; CGGA: Chinese Glioma Genome Atlas; CFA: Colony formation assay; CI: Confidence interval; CDK1: Cyclin-dependent kinase 1; CYP2D6: Cytochrome P450 2D6; DAVID: Database for Visualization, Annotation and Integrated Discovery; DTP: Developmental toxicity potential; DS4.5: Discovery Studio 4.5; TOP2A: DNA topoisomerase II alpha; DMEM: Dulbecco’s modified Eagle’s medium; EMT: Epithelial-mesenchymal transition; FBS: Fetal bovine serum; GEO: Gene Expression Omnibus; GO: Gene Ontology; GSEA: Gene Set Enrichment Analysis; GS: Gene Significance; GBM: Glioblastoma; HR: Hazard ratio; KDR: Kinase insert domain receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; LINCS: Linear constraint solver; MRI: Magnetic resonance imaging; MM: Module Membership; MCODE: Molecular Complex Detection; NTP: National Toxicology Program; NES: Normal enrichment score; NPT: Normal pressure and temperature; OS: Overall survival; PME: Particle mesh ewald; PBS: Phosphate-buffered saline; PPB: Plasma protein binding; PFS: Progression-free survival; PPI: Protein-protein interaction; RASSF1A: RAS-association domain family 1, isoform A; RMSD: Root mean-square deviation; STRING: Search Tool for the Retrieval of Interacting Genes; TCGA: The Cancer Genome Atlas; TOPKAT: Toxicity Prediction by Komputer Assisted Technology; TEM: Transmission Electron Microscope; VEGFR-2: Vascular endothelial growth factor receptor 2; WGCNA: Weighted gene co-expression network analysis; WHO: World Health Organization.