Inhibitory effects of 2′-nitroflavone and apigenin on EGFR signaling in breast cancer cells

The epidermal growth factor receptor (EGFR) is frequently dysregulated in certain cancers, including breast cancer. Gefitinib, an EGFR tyrosine kinase inhibitor (TKI) used in non-small cell lung cancer, was proposed for breast cancer treatment. The use of TKI in combination with other compounds may improve therapy effectiveness and delay drug-resistance development. Since many flavonoids exhibit anticancer effects, their combination with EGFR inhibitors was suggested for the treatment of certain tumors. In the current work, we assessed the effects of apigenin and 2'-nitroflavone as monotherapy in hormone-sensitive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. These flavones inhibited cell growth and negatively modulated EGFR signaling. Since 2'-nitroflavone exhibited a higher potency, we evaluated the effect of a combined therapy with gefitinib. This treatment led to a stronger cell growth inhibition than drugs alone, with combination index values suggesting synergistic interactions, particularly at lower concentrations. An enhancement of the proapoptotic effect was also observed. Thus, 2'-nitroflavone and apigenin exerted antitumor effects in breast cancer cells that were mediated, at least in part, by negative modulation of EGFR signaling. Moreover, a synergistic growth inhibitory effect for the combination of 2'-nitroflavone with gefitinib was found, supporting further investigation of these compounds in preclinical models of breast cancer.