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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 Zhong1,2,3, Yang Bai1,4, Bo Wu4,5, Junliang Ge4, Shanshan Jiang6, Weihang Li4, Xinhui Wang7, Junan Ren4, Haiyang Xu1, Yong Chen1, Gang Zhao1
  • 1Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China
  • 2Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
  • 3Department of Bioinformatics, Harvard Medical School, Boston, MA 02115, USA
  • 4Clinical College, Jilin University, Changchun, China
  • 5Department of Orthopedics, The First Hospital of Jilin University, Changchun, China
  • 6Institute of Zoology, China Academy of Science, Beijing, China
  • 7Department of Oncology, The First Hospital of Jilin University, Changchun, China
Received: July 30, 2019Accepted: October 28, 2019Published: November 9, 2019
https://doi.org/10.18632/aging.102422

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.