The co-treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells.

Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway. The results presented herein revealed that the combination of metformin and flavone significantly inhibited cell viability, and increased apoptosis of human breast cancer cells compared with metformin or flavone alone. The combination decreased the protein expression of MDMX, activated p53 through the PI3K/AKT signaling pathway, regulated p53 downstream target genes Bcl-2 apoptosis regulator, BCL2 associated X apoptosis regulator and cleaved caspase3, subsequently inducing apoptosis in MDA-MB-231 and MCF-7 breast cancer cells. These results indicated that dietary flavone may potentiate breast cancer cell apoptosis induced by metformin, and PI3K/AKT is involved in regulating MDMX/p53 signaling. This data suggests that dietary supplementary of flavone is a promising strategy for metformin mediated anticancer effects.