Bioactive treatments against chronic myeloid leukemia from Hypericum lancasteri targeting p53 pathway

The discovery of biologically active compounds from plants is an emerging challenge in natural pharmaceutical development. Here, we report the comprehensive strategy for undescribed compounds discovery targeting p53 pathway from Hypericum lancasteri against chronic myeloid leukemia (CML). The UHPLC-Q-TOF-MS analysis of H. lancasteri obtained 44 compounds information in positive and negative ion modes. Besides, three new compounds (1-3) together with two known derivatives (4 and 5) were obtained and identified by further phytochemical research. The dichloromethane extraction part (DEP) of H. lancasteri as well as compounds 1, 4, and 5 showed cytotoxic activity against CML cell line K562. For the mechanism of action, the potential affinity of DEP with p53 ubiquitinase MDM2 DEP was uncovered in surface plasmon resonance (SPR) experiment, and DEP may induce nucleus damage of K562 cells in fluorescence staining. Furthermore, DEP demonstrated therapeutic efficacy on K562 tumor-bearing mice in vivo. The mitochondria destruction ability of DEP was then indicated by transmission electron microscopy (TEM) analysis, which may further promote the p53 dependent apoptosis. Compounds 1, 4, and 5 may accumulate p53 protein through competitive binding with MDM2 as well as inhibit CML by p53 related cell apoptosis and cell cycle blocking. This study assembled multiple approach to discover bioactive compounds from H. lancasteri and shed new example on novel treatments for CML targeting p53 pathway.