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Identifying candidate agents for lung adenocarcinoma by walking the human interactome

Authors Sun Y, Zhang R, Jiang Z, Xia R, Zhang J, Liu J, Chen F

Received 29 September 2015

Accepted for publication 9 March 2016

Published 1 September 2016 Volume 2016:9 Pages 5439—5450

DOI https://doi.org/10.2147/OTT.S97357

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Wei An

Peer reviewer comments 3

Editor who approved publication: Dr William Cho


Yajiao Sun,1 Ranran Zhang,2 Zhe Jiang,1 Rongyao Xia,1 Jingwen Zhang,1 Jing Liu,1 Fuhui Chen1

1Department of Respiratory, The Second Affiliated Hospital of Harbin Medical University, 2Department of Respiratory, Harbin First Hospital, Harbin, People’s Republic of China

Abstract: Despite recent advances in therapeutic strategies for lung cancer, mortality is still increasing. Therefore, there is an urgent need to identify effective novel drugs. In the present study, we implement drug repositioning for lung adenocarcinoma (LUAD) by a bioinformatics method followed by experimental validation. We first identified differentially expressed genes between LUAD tissues and nontumor tissues from RNA sequencing data obtained from The Cancer Genome Atlas database. Then, candidate small molecular drugs were ranked according to the effect of their targets on differentially expressed genes of LUAD by a random walk with restart algorithm in protein–protein interaction networks. Our method identified some potentially novel agents for LUAD besides those that had been previously reported (eg, hesperidin). Finally, we experimentally verified that atracurium, one of the potential agents, could induce A549 cells death in non-small-cell lung cancer-derived A549 cells by an MTT assay, acridine orange and ethidium bromide staining, and electron microscopy. Furthermore, Western blot assays demonstrated that atracurium upregulated the proapoptotic Bad and Bax proteins, downregulated the antiapoptotic p-Bad and Bcl-2 proteins, and enhanced caspase-3 activity. It could also reduce the expression of p53 and p21Cip1/Waf1 in A549 cells. In brief, the candidate agents identified by our approach may provide greater insights into improving the therapeutic status of LUAD.

Keywords:
lung adenocarcinoma, drug repositioning, bioinformatics, protein–protein interaction network, atracurium

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