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

Hye Lin Kim; Kyung Hwa Jeon; Kyu Yeon Jun; Yongmun Choi; Dae Kee Kim; Younghwa Na; Youngjoo Kwon

doi:10.1016/j.canlet.2012.06.004

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

Hye Lin Kim, Kyung Hwa Jeon, Kyu Yeon Jun, Yongmun Choi, Dae Kee Kim, Younghwa Na, Youngjoo Kwon

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English
Pages (from-to)	72-79
Number of pages	8
Journal	Cancer Letters
Volume	325
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2012.06.004
State	Published - 1 Dec 2012

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0071926, 2009-0066925, 2010-0002646) and by the Ewha Global Top5 Grant 2011 of Ewha Womans University.

Keywords

Fluoroquinophenoxazine derivative
Gastric cancer
Human epidermal growth factor receptor 2
Topoisomerase IIα

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10.1016/j.canlet.2012.06.004

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

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.",

keywords = "Fluoroquinophenoxazine derivative, Gastric cancer, Human epidermal growth factor receptor 2, Topoisomerase IIα",

author = "Kim, {Hye Lin} and Jeon, {Kyung Hwa} and Jun, {Kyu Yeon} and Yongmun Choi and Kim, {Dae Kee} and Younghwa Na and Youngjoo Kwon",

note = "Funding Information: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0071926, 2009-0066925, 2010-0002646) and by the Ewha Global Top5 Grant 2011 of Ewha Womans University.",

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AU - Kim, Hye Lin

AU - Jeon, Kyung Hwa

AU - Jun, Kyu Yeon

AU - Choi, Yongmun

AU - Kim, Dae Kee

AU - Na, Younghwa

AU - Kwon, Youngjoo

N1 - Funding Information: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0071926, 2009-0066925, 2010-0002646) and by the Ewha Global Top5 Grant 2011 of Ewha Womans University.

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

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