Human estrogen receptor alpha (ERα) targeted cyclic peptides inhibit cell growth and induce apoptosis in MCF-7 cells

Abstract

Human estrogen receptor alpha (ERα) is considered an important target, especially in the treatment of breast cancer, as it has a vital role in cancer development. ERα-targeted therapies generally target the ligand binding domain (LBD) of ERα. However, over time, cells develop resistance to this mechanism alternative approaches to inhibit ERα activity target ERα–DNA or ERα–cofactor interactions. Inhibitors of ERα–cofactor interactions are designed by targeting the hydrophobic hollow region of the receptor box LXXLL motif. In this context, helix-stabilized cyclic peptides (SPs) designed with in silico approaches were obtained by solid phase peptide synthesis. The effects of SPs on MCF-7 cells were examined with MTT and ATP, and qPCR and flow cytometry were used for further analysis. Our results demonstrated that the SPs were effective only in MCF-7 cells expressing ERα. In addition, cyclic peptide combinations (SPCs) showed anti-proliferative and toxic effects on MCF-7 cells. The impact of SPCs with the highest inhibitory effect in MCF-7 cells on ERα-related genes and markers of apoptosis was revealed. Moreover, the flow cytometry analysis result used to examine apoptotic cells proved the apoptosis of SPCs in MCF-7 cells. These findings suggest that our novel SPs, which inhibit coactivator interactions of ERα, induce apoptosis of MCF-7 cells. Thus, considering this strong effect of SPs in the inhibition of receptors, it is pointed out that they can be further developed as an alternative to current clinical treatments or as an auxiliary approach in the generating of new targeted peptide-based therapies.