期刊
RSC ADVANCES
卷 7, 期 76, 页码 48404-48419出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7ra09825a
关键词
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资金
- Program for Changjiang Scholars and Innovative Research Team in University [IRT_14R27]
- National Natural Science Foundation of China [31470384, 31171161, 31670298]
- Fundamental Research Funds for the Central Universities [020814380002]
Over the past few decades, the human epidermal growth factor receptor (EGFR) has been established as an attractive target for non-small cell lung cancer (NSCLC) therapy. Nevertheless, the approved EGFR inhibitors, gefitinib or erlotinib have shown minimum clinical activity to breast cancer patients, who also highly expressed EGFR. In this study, we designed and synthesized a series of novel formononetin derivatives by reference to the binding mode of lapatinib to EGFR. In vitro EGFR and cell growth inhibition assay demonstrated that compound 4v exhibited the most potent anti-EGFR (IC50 = 14.5 nM) and anti-proliferation activity (IC50 = 5.44 +/- 1.28 mu M) against MDA-MB-231 cell line, which was comparable to that of lapatinib (EGFR, IC50 = 5.6 nM; MDA-MB-231, IC50 = 2.48 +/- 1.04 mu M). Further biological experiment results demonstrated that 4v could effectively induce apoptosis, inhibit proliferation and migration in MDA-MB-231 cells through targeting EGFR and then blocking the downstream signaling pathways, EGFR/PI3K/Akt/Bad, EGFR/ERK and EGFR/PI3K/Akt/beta-catenin, respectively. However, it had no significant influence on cell cycle distribution and the related proteins (Cyclin A, Cyclin D1, CDK4) expression. In vivo anti-tumor results also preliminarily confirmed the effectiveness of 4v in tumor chemotherapy in mice and indicated its potential as a new EGFR inhibitor in the treatment of MDA-MB-231 malignant tumor.
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