Rugosin E, an ellagitannin, inhibits MDA-MB-231 human breast cancer cell proliferation and induces apoptosis by inhibiting nuclear factor-κB signaling pathway

Abstract

In this study, we first report the chemopreventive effect of rugosin E in human breast cancer cell line, MDA-MB-231. Treatment with rugosin E decreased the cell proliferation of MDA-MB-231 cells in a dose-dependent manner. Rugosin E treatment arrested MDA-MB-231 cells at G0/G1 phase. This effect was strongly associated with concomitant decrease in the level of cyclin D1, cyclin D2, cyclin E, cdk2, cdk4, and cdk6, and increase of p21/WAF1. In addition, rugosin E also induced apoptotic cell death. Rugosin E increased in the expression of Bax, Bak, and Bcl-Xs, but decreased the levels of Bcl-2 and Bcl-X L, and subsequently triggered mitochondria apoptotic pathway (release of cytochrome c, activation of caspase-9, and caspase-3). In addition, pre-treatment of cells with caspase-9 inhibitor blocked rugosin E-induced cell proliferation and apoptosis, indicating caspase-9 activation was involved in rugosin E-mediated MDA-MB-231 cells apoptosis. Rugosin E inhibited the constitutively activated and inducible NF-κB in both its DNA-binding activity and transcriptional activity. Furthermore, rugosin E also inhibited the TNF-α-activated NF-κB-dependent reporter gene expression of cyclin D1, c-Myc, XIAP, Bcl-2, and Bcl-X L were all downregulated by rugosin E. Our results indicated that rugosin E inhibits the activation of NF-κB, and this may provide a molecular basis for drug development in the prevention and treatment of cancer by rugosin E.