A novel anthraquinone‑quinazoline hybrid7B blocks breast cancer metastasis and EMT via targeting EGFR and Rac1.

Abstract

At present, effective therapeutic drugs for triple‑negative breast cancer (TNBC) are lacking due to the absence of identified or available targets. Therefore, the present study aimed to identify key molecular targets and a specific targeted therapeutic drug to aid with the development of novel therapeutic strategies for TNBC. Based on the high expression of EGFR and Rac1 in TNBC and inspired by a novel antitumor strategy termed combi‑targeting, novel anthraquinone‑quinazoline hybrid7B was synthesized to simultaneously target EGFR and Rac1. It was hypothesized that hybrid7B may possess enhanced potency compared with its parent compounds. Breast cancer cell viability was detected by performing MTT assays. Flow cytometry was conducted to detect the effects of hybrid7B on the cell cycle, apoptosis and the mitochondrial outer membrane potential. Ultrastructural alterations were observed by transmission electron microscopy. Cell invasion and migration were assessed by performing Transwell and wound‑healing assays, respectively. The expression levels of epithelial‑mesenchymal transition (EMT) markers and metastasis‑related proteins were detected by western blotting. Compared with Rhein and gefitinib, hybrid7B displayed superior antiproliferative activity in MDA‑MB‑231 cells with an IC50 value of 2.31µM, which was 14‑fold higher compared with the EGFR tyrosine kinase inhibitor gefitinib. Further experiments demonstrated that hybrid7B significantly reduced the mitochondrial membrane potential, enhanced MDA‑MB‑231 cell apoptosis and induced cell cycle arrest at the G2/Mphase compared with the control group. Typical morphological alterations of apoptotic cells were observed in hybrid7B‑treated MDA‑MB‑231 and MCF‑7 cells. Compared with the control group, hybrid7B significantly inhibited MDA‑MB‑231 cell invasion and migration by downregulating Rac1, EGFR, matrix metalloproteinases, snail family transcriptional repressor1, Vimentin and β‑catenin protein expression levels, and upregulating E‑cadherin protein expression levels. The present study demonstrated that hybrid7B inhibited TNBC cell migration and invasion by reversing EMT and targeting EGFR and Rac1; therefore, hybrid7B may serve as a promising therapeutic agent for TNBC.