In search of underlying mechanisms and potential drugs of melphalan-induced vascular toxicity through retinal endothelial cells using bioinformatics approach
- 143 Downloads
We aimed to explore molecular mechanism and drug candidates of vascular toxicities associated with melphalan after treating human retinal endothelial cells (RECs). GSE34381 microarray data was firstly downloaded and used to identify the differentially expressed genes (DEGs) in human REC treated with melphalan vs. untreated cells by limma package in R language. The transcription network was constructed based on TRANSFAC database and the top five transcription factors (TFs) were select with a measure of regulatory impact factor, followed by the construction of function modules. Gene ontology enrichment analyses were performed to explore the enriched functions. Connectivity Map analysis was conducted to predict the potential drugs overcoming the melphalan’s actions on REC. Totally, 75 DEGs were identified, including 70 up-regulated and five down-regulated genes. Transcription network with 1311 nodes and 1875 edges was constructed and the top five TFs were CREM, MYC, FLI1, NF-κB1, and JUN. Functional modules indicated that NF-κB1 and MYC were the important nodes. The upregulated genes as well as the genes involved in the modules mainly participated in biological process of immune response, cell proliferation, and cell motion. Five small molecules were predicted to be potential drug candidates, including doxorubicin, fipexide, daunorubicin, tiabendazole, and GW-8510. Based on these results, we speculate that NF-κB1 and MYC might involve in the molecular mechanism of vascular toxicity induced by melphalan through regulating their target genes. Five small molecules might be drug candidates to overcome the melphalan-induced vascular toxicity via targeting to MYC and JUN.
KeywordsRetinoblastoma Melphalan Transcription network Transcription factor Connectivity Map analysis
This study was supported by the Hubei Provincial Natural Science Foundation of China (No. 2014CFB366).
Compliance with ethical standards
Conflicts of interest
- 6.Vajzovic LM, Murray TG, Aziz-Sultan MA, Schefler AC, Fernandes CE, Wolfe SC, et al. Clinicopathologic review of enucleated eyes after intra-arterial chemotherapy with melphalan for advanced retinoblastoma. Arch Ophthalmol. 2010;128(12):1619–23. doi: 10.1001/archophthalmol.2010.296.CrossRefPubMedGoogle Scholar
- 11.Scutaru AM, Wenzel M, Scheffler H, Wolber G, Gust R. Optimization of the N-lost drugs melphalan and bendamustine: synthesis and cytotoxicity of a new set of dendrimer-drug conjugates as tumor therapeutic agents. Bioconjug Chem. 2010;21(10):1728–43. doi: 10.1021/bc900453f.CrossRefPubMedGoogle Scholar
- 12.Steinle JJ, Zhang Q, Thompson KE, Toutounchian J, Yates CR, Soderland C, et al. Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis. Invest Ophthalmol Vis Sci. 2012;53(4):2439–45. doi: 10.1167/iovs.12-9466.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Zhang Q, Jiang Y, Toutounchian J, Wilson MW, Morales-Tirado V, Miller DD, et al. Novel quinic acid derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling. Invest Ophthalmol Vis Sci. 2013;54(9):5937–43.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.da Huang W, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, et al. The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 2007;8(9):R183. doi: 10.1186/gb-2007-8-9-r183.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Van de Stolpe A, Caldenhoven E, Stade BG, Koenderman L, Raaijmakers J, Johnson JP, et al. 12-O-tetradecanoylphorbol-13-acetate-and tumor necrosis factor alpha-mediated induction of intercellular adhesion molecule-1 is inhibited by dexamethasone. Functional analysis of the human intercellular adhesion molecular-1 promoter. J Biol Chem. 1994;269(8):6185–92.PubMedGoogle Scholar
- 38.Kipshidze NN, Iversen P, Kim HS, Yiazdi H, Dangas G, Seaborn R, et al. Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model. Catheter Cardiovasc Interv. 2004;61(4):518–27.CrossRefPubMedGoogle Scholar