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A-62176, a potent topoisomerase inhibitor, inhibits the expression of human epidermal growth factor receptor 2

Title
A-62176, a potent topoisomerase inhibitor, inhibits the expression of human epidermal growth factor receptor 2
Authors
Kim H.-L.Jeon K.-H.Jun K.-Y.Choi Y.Kim D.-K.Na Y.Kwon Y.
Ewha Authors
김대기권영주전규연
SCOPUS Author ID
김대기scopus; 권영주scopus
Issue Date
2012
Journal Title
Cancer Letters
ISSN
0304-3835JCR Link
Citation
vol. 325, no. 1, pp. 72 - 79
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 p27Kip1 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. © 2012 Elsevier Ireland Ltd.
DOI
10.1016/j.canlet.2012.06.004
Appears in Collections:
약학대학 > 약학과 > Journal papers
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