F1012-2 inhibits the growth of triple negative breast cancer through induction of cell cycle arrest, apoptosis, and autophagy

Abstract

Sesquiterpene lactones (SLs) are plant-derived constituents that have been proved to have potential antitumour activity. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. Here, we report that F1012-2, a novel SL active fraction, isolated from Eupatorium lindleyanum DC., can significantly inhibit the growth of triple-negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) but has no obvious inhibitory effect on the growth of human mammary epithelial cells (MCF-10A). The related mechanisms on cell growth inhibition of F1012-2 were demonstrated by inducing apoptosis in a caspase-dependent manner through the intrinsic pathway and extrinsic pathway. F1012-2 could also activate autophagy in TNBC cells. Simultaneously, we found that F1012-2-induced apoptosis was enhanced by inhibition of autophagy. Furthermore, F1012-2 could induce cell cycle arrest at G2/M phase with decreasing expression of cyclin B1, cdc2, and upregulating p21, p-cdc2. Also, F1012-2 activated Akt and p38 signalling pathways. In vivo, F1012-2 exhibited a potential antitumour effect in MDA-MB-231 xenografts without apparent toxicity. Taken together, our results identified that F1012-2 inhibited cell growth via multiple signalling pathways in vitro and in vivo. These data suggest that F1012-2 may be a potential natural active fraction for the treatment of TNBC.