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 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.

► A-62176, discovered from SEAP assay screening, inhibits the ESX-Sur2 interaction.
► A-62176 inhibits HER2 gene transcription and HER2 receptor protein expression.
► A-62176 attenuates HER2 autophosphorylation and HER2-mediated downstream signals.
► A-62176 induces G1 arrest through decrease of cyclin D1 and induction of p27Kip1.
► A-62176 shows a strong synergistic activity with doxorubicin.