A Daidzein Metabolite, 6,7,4 '-Trihydroxyisoflavone Inhibits Cellular Proliferation through Cell Cycle Arrest and Apoptosis Induction in MCF10CA1a Human Breast Cancer Cells

Abstract

Despite recent findings of hepatic daidzein metabolites on prevention of skin and colon cancers, little study has been performed on breast cancer. In this study, we found that 6,7,4'-trihydroxyisoflavone, one of the major hepatic metabolite of the daidzein more significantly inhibited proliferation of MCF10CA1 a human estrogen receptor (ER)-negative breast cancer cells, which was derived from arresting cell cycle at S- and G2/M phase. Cyclins and cyclin-dependent kinases (CDKs) involved in S- and G2/M phases, including cyclins A, B, E, CDK1 and CDK2 were regulated by 6,7,4'-trihydroxyisoflavone as well as CDK inhibitor, p21 and p27, in a dose-dependent manner. In addition, 6,7,4'-trihydroxyisoflavone induced apoptosis by enhancing death receptor4 (DR4) expression and suppressing the X-linked inhibitor of apoptosis protein, leading to poly ADP-ribose polymerase cleavage. Taken together, 6,7,4'-trihydroxyisoflavone inhibits cell proliferation via arresting cell cycle at S- and G2/M phases and inducing apoptosis in MCF10CA1 a human breast cancer cells. These results suggest that the hepatic metabolite of daidzein, 6,7,4'-trihydroxyisoflavone, may be considered as a more potent agent in inhibiting ER-negative breast carcinogenesis.