Abstract
Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.
Keywords:
Ewing sarcoma; TrkA; TrkB; neurotrophin; neurotrophin receptor.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Azepines / pharmacology
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Benzamides / pharmacology
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Brain-Derived Neurotrophic Factor / biosynthesis*
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Brain-Derived Neurotrophic Factor / genetics
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Carbazoles / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Doxorubicin / pharmacology
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Enzyme Inhibitors / pharmacology
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Etoposide / pharmacology
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Humans
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Indole Alkaloids / pharmacology
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Membrane Glycoproteins / antagonists & inhibitors*
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Nerve Growth Factor / biosynthesis*
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Nerve Growth Factor / genetics
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RNA, Messenger / biosynthesis
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Receptor, trkA / antagonists & inhibitors*
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Receptor, trkA / biosynthesis
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Receptor, trkA / genetics
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Receptor, trkB / antagonists & inhibitors*
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Receptor, trkB / biosynthesis
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Receptor, trkB / genetics
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Sarcoma, Ewing / drug therapy*
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Sarcoma, Ewing / pathology
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Tubulin / metabolism
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Vincristine / pharmacology
Substances
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ANA 12 compound
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Antineoplastic Agents
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Azepines
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Benzamides
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Brain-Derived Neurotrophic Factor
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Carbazoles
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Enzyme Inhibitors
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Indole Alkaloids
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Membrane Glycoproteins
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NGF protein, human
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NTRK1 protein, human
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RNA, Messenger
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TUBB3 protein, human
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Tubulin
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Vincristine
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Etoposide
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BDNF protein, human
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Doxorubicin
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Nerve Growth Factor
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staurosporine aglycone
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Receptor, trkA
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Receptor, trkB
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tropomyosin-related kinase-B, human