A-62176, a potent topoisomerase inhibitor, inhibits the expression of human epidermal growth factor receptor 2.
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.
College of Pharmacy, Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
Hye-Lin
HL
Kim
Kyung-Hwa
KH
Jeon
Kyu-Yeon
KY
Jun
Yongmun
Y
Choi
Dae-Kee
DK
Kim
Younghwa
Y
Na
Youngjoo
Y
Kwon
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D015363:Quinolones / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000951:Antigens, Neoplasm; D019938:Cyclin D1; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D056892:Mediator Complex; D020929:Mitogen-Activated Protein Kinase Kinases; D010078:Oxazines; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D015363:Quinolones; D018719:Erb-b2 Receptor Tyrosine Kinases; D059003:Topoisomerase Inhibitors; D014157:Transcription Factors; C105529:ELF3 protein, human; C492159:MED23 protein, human; C413374:p27 antigen; C091925:A 62176; C508053:ERBB2 protein, human