Cytotoxic Components From Hypericum Elodeoides Targeting Rxr Alpha And Inducing Hela Cell Apoptosis Through Caspase-8 Activation And Parp Cleavage

To find small-molecule regulators of RXR alpha, a phytochemical study of Hypericum elodeoides was conducted. Fifteen compounds, including the new 1 and 6, were isolated from the whole plant of H. elodeoides. The absolute configuration of 1 was assigned by comparison of experimental and calculated ECD data. Compounds 1 and 6 exhibited concentration-dependent inhibitory effects on RXR alpha transcription and selectively inhibited the proliferation of HeLa cells. Western blot analysis suggested that 1 and 6 induced apoptosis of HeLa cells with time- and dose-dependent PARP cleavage. A caspase activation assay indicated that these two compounds triggered caspase-8 activation to induce apoptosis by the extrinsic pathway. Molecular docking results suggested that 1 and 6 interacted with the Arg319 moiety of RXR alpha-LBD. Ligands binding to RXR alpha have shown promise in the discovery of anticancer drugs. A fluorescence quenching assay indicated the binding of 1 and 6 to the RXR alpha with the binding constant (K-D) fitted as 68.3 and 14.0 mu M, respectively. A preliminary SAR study of the isolates was conducted to enhance the knowledge of the RXR alpha ligands. Thus, 1 and 6 might act as the small-molecule regulators of RXR alpha, which target RXR alpha and mediate HeLa cell apoptosis through the extrinsic pathways.