Abstract
HER2 overexpression is observed in ∼6-35% of all gastric cancers, while co-amplification of topoisomerase IIα occurs in ∼32-90% of all cancers with HER2 amplification. The present study reports that HER2 expression is down-regulated by A-62176, a fluoroquinophenoxazine derivative that we previously demonstrated to inhibit topoisomerase I and IIα. The results suggest that A-62176 inhibits the interaction between the ESX, an ets transcription factor, and its co-activator Sur2, leading to the attenuation of HER2-mediated phosphorylation of MAPK/Akt. A-62176 arrests the cell cycle in the G1 phase via the down-regulation of cyclin D1 and the up-regulation of p27(Kip1) in NCI-N87 gastric cancer cells. The combination of A-62176 with doxorubicin provides a strong synergistic activity. We propose that A-62176 is a dual inhibitor that impairs the expression of HER2 and restrains the activity of topoisomerase IIα. Our results may lead to the rational design of anticancer molecules targeting a subgroup of gastric cancer cells overexpressing both HER2 and topoisomerase IIα.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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DNA Topoisomerases, Type I / genetics
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DNA Topoisomerases, Type I / metabolism*
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / drug effects
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Doxorubicin / pharmacology
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G1 Phase / drug effects
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G1 Phase / genetics
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HEK293 Cells
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Humans
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Mediator Complex / genetics
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Mediator Complex / metabolism
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Oxazines / pharmacology*
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Phosphorylation / drug effects
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Proliferating Cell Nuclear Antigen / genetics
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Proliferating Cell Nuclear Antigen / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-ets
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Quinolones / pharmacology*
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / genetics
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Signal Transduction / drug effects
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Stomach Neoplasms / drug therapy
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism
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Topoisomerase Inhibitors / pharmacology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation / drug effects
Substances
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Antigens, Neoplasm
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DNA-Binding Proteins
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ELF3 protein, human
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MED23 protein, human
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Mediator Complex
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Oxazines
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Proliferating Cell Nuclear Antigen
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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Quinolones
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Topoisomerase Inhibitors
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Transcription Factors
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p27 antigen
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Cyclin D1
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A 62176
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Doxorubicin
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ERBB2 protein, human
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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DNA Topoisomerases, Type I
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DNA Topoisomerases, Type II