Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-04-09

AUTHORS

V Damiano, R Rosa, L Formisano, L Nappi, T Gelardi, R Marciano, I Cozzolino, G Troncone, S Agrawal, B M Veneziani, S De Placido, R Bianco, G Tortora

ABSTRACT

Background:Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors.Methods:We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells.Results:Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions.Conclusion:A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting. More... »

PAGES

1616-1623

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/bjc.2013.153

DOI

http://dx.doi.org/10.1038/bjc.2013.153

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1021470202

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23571736


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32 schema:description Background:Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors.Methods:We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells.Results:Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions.Conclusion:A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.
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39 RCC
40 RCC cell lines
41 Toll-like receptor 9 agonist
42 VEGF secretion
43 VHL
44 activity
45 agonists
46 angiogenesis
47 antiangiogenic activity
48 antiangiogenic effects
49 antitumour
50 antitumour activity
51 approach
52 carcinoma
53 carcinoma therapy
54 cell carcinoma
55 cell function
56 cell lines
57 cells
58 clinical setting
59 combination
60 direct antiangiogenic effects
61 effect
62 endothelial cell function
63 endothelial cells
64 epidermal growth factor receptor
65 everolimus
66 factor inhibitors
67 factor receptor
68 function
69 gene status
70 growth
71 growth factor inhibitors
72 growth factor receptor
73 human RCC
74 human umbilical vein endothelial cells
75 inhibition
76 inhibitors
77 inhibitory effect
78 lines
79 mammalian target
80 mice
81 model
82 mouse survival
83 mutant cells
84 mutant models
85 nude mice
86 oligonucleotide
87 prolongation
88 rapamycin
89 receptor 9 agonist
90 receptors
91 reduction
92 renal cell carcinoma
93 renal cell carcinoma therapy
94 secretion
95 setting
96 signal transduction
97 signaling
98 status
99 successful approach
100 survival
101 synergistic inhibitory effect
102 target
103 therapy
104 transduction
105 treatment
106 tumor growth
107 tumor xenografts
108 umbilical vein endothelial cells
109 vascular endothelial growth factor inhibitors
110 vein endothelial cells
111 vitro growth
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