Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 5/2016

01-05-2016 | Original Article

In search of underlying mechanisms and potential drugs of melphalan-induced vascular toxicity through retinal endothelial cells using bioinformatics approach

Authors: Yang Yang, Yiqiao Xing, Chaoqun Liang, Liya Hu, Fei Xu, Qi Mei

Published in: Tumor Biology | Issue 5/2016

Login to get access

Abstract

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.
Literature
1.
2.
3.
Jehanne M, Brisse H, Gauthier-Villars M, Lumbroso-le Rouic L, Freneaux P, Aerts I. Retinoblastoma: recent advances. Bull Cancer. 2014;101(4):380–7.PubMed
4.
Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93(9):1129–31.CrossRefPubMed
5.
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.CrossRefPubMed
7.
Reese AB, Hyman GA, Tapley ND, Forrest AW. The treatment of retinoblastoma by x-ray and triethylene melamine. AMA Arch Ophthalmol. 1958;60(5):897–906.CrossRefPubMed
8.
Kiribuchi M. Retrograde infusion of anti-cancer drugs to ophthalmic artery for intraocular malignant tumors. Nihon Ganka Gakkai Zasshi. 1966;70(11):1829–33.PubMed
9.
Samuels BL, Bitran JD. High-dose intravenous melphalan: a review. J Clin Oncol. 1995;13(7):1786–99.CrossRefPubMed
10.
Doll DC, Ringenberg QS, Yarbro J. Vascular toxicity associated with antineoplastic agents. J Clin Oncol. 1986;4(9):1405–17.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
14.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41(Database issue):D991–5. doi:10.​1093/​nar/​gks1193.CrossRefPubMed
15.
16.
Gautier L, Cope L, Bolstad BM, Irizarry RA. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20(3):307–15.CrossRefPubMed
17.
18.
19.
20.
Wingender E, Dietze P, Karas H, Knüppel R. TRANSFAC: a database on transcription factors and their DNA binding sites. Nucleic Acids Res. 1996;24(1):238–41.CrossRefPubMedPubMedCentral
21.
22.
23.
24.
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006;313(5795):1929–35.CrossRefPubMed
25.
Shields CL, Bianciotto CG, Jabbour P, Griffin GC, Ramasubramanian A, Rosenwasser R, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 2, treatment complications. Arch Ophthalmol. 2011;129(11):1407–15.CrossRefPubMed
26.
Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol. 2002;64(5–6):883–8.CrossRefPubMed
27.
O’Neill LA, Kaltschmidt C. NF-kB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 1997;20(6):252–8.CrossRefPubMed
28.
Soultati A, Mountzios G, Avgerinou C, Papaxoinis G, Pectasides D, Dimopoulos MA, et al. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. Cancer Treat Rev. 2012;38(5):473–83. doi:10.​1016/​j.​ctrv.​2011.​09.​002.CrossRefPubMed
29.
30.
Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells implications for vascular disease. Circulation. 2001;103(22):2717–23.CrossRefPubMed
31.
Staunton DE, Marlin SD, Stratowa C, Dustin ML, Springer TA. Primary structure of ICAM-1 demonstrates interaction between members of the immunoglobulin and integrin supergene families. Cell. 1988;52(6):925–33.CrossRefPubMed
32.
Duckers HJ, Boehm M, True AL, Yet SF, San H, Park JL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001;7(6):693–8. doi:10.​1038/​89068.CrossRefPubMed
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.PubMed
34.
Liu MT, Keirstead HS, Lane TE. Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. J Immunol. 2001;167(7):4091–7.CrossRefPubMed
35.
36.
37.
Amati B, Land H. Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death. Curr Opin Genet Dev. 1994;4(1):102–8.CrossRefPubMed
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.CrossRefPubMed
39.
Doll DC, Yarbro JW. Vascular toxicity associated with chemotherapy and hormonotherapy. Curr Opin Oncol. 1994;6(4):345–50.CrossRefPubMed
40.
Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Øvervatn A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171(4):603–14.CrossRefPubMedPubMedCentral
41.
42.
Murata T, Yamawaki H, Yoshimoto R, Hori M, Sato K, Ozaki H, et al. Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study. Life Sci. 2001;69(22):2685–95.CrossRefPubMed
43.
Wojcik T, Buczek E, Majzner K, Kolodziejczyk A, Miszczyk J, Kaczara P, et al. Comparative endothelial profiling of doxorubicin and daunorubicin in cultured endothelial cells. Toxicol In Vitro. 2015;29(3):512–21.CrossRefPubMed
44.
Jr FF, Jarvis WD, Grant S. Growth arrest and non-apoptotic cell death associated with the suppression of c-myc expression in MCF-7 breast tumor cells following acute exposure to doxorubicin. Biochem Pharmacol. 1996;51(7):931–40.CrossRef
45.
Javelaud D, Wietzerbin J, Delattre O, Besançon F. Induction of p21Waf1/Cip1 by TNF|[alpha]| requires NF-|[kappa]|B activity and antagonizes apoptosis in Ewing tumor cells. Oncogene. 2000;19(1):61–8.CrossRefPubMed
46.
Cha HJ, Byrom M, Mead PE, Ellington AD, Wallingford JB, Marcotte EM. Evolutionarily repurposed networks reveal the well-known antifungal drug thiabendazole to be a novel vascular disrupting agent. Plos Biol. 2012;10(8):255–70.CrossRef
47.
Dunn C, Wiltshire C, MacLaren A, Gillespie DA. Molecular mechanism and biological functions of c-Jun N-terminal kinase signalling via the c-Jun transcription factor. Cell Signal. 2002;14(7):585–93.CrossRefPubMed
48.
Fogelstrand P, Feral CC, Zargham R, Ginsberg MH. Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2). J Exp Med. 2009;206(11):2397–406.CrossRefPubMedPubMedCentral
Metadata
Title
In search of underlying mechanisms and potential drugs of melphalan-induced vascular toxicity through retinal endothelial cells using bioinformatics approach
Authors
Yang Yang
Yiqiao Xing
Chaoqun Liang
Liya Hu
Fei Xu
Qi Mei
Publication date
01-05-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 5/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4444-5

Other articles of this Issue 5/2016

Tumor Biology 5/2016 Go to the issue

Original Article

Overexpression of microRNA-30a-5p inhibits liver cancer cell proliferation and induces apoptosis by targeting MTDH/PTEN/AKT pathway

Original Article

Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer

Original Article

Upregulated expression of long noncoding RNA SNHG15 promotes cell proliferation and invasion through regulates MMP2/MMP9 in patients with GC

Original Article

Differential effects of c-myc and ABCB1 silencing on reversing drug resistance in HepG2/Dox cells

Review

Profiling cell-free and circulating miRNA: a clinical diagnostic tool for different cancers

Erratum

Erratum to: Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits