RETRACTED ARTICLE: Jacarelhyperol A induced apoptosis in leukaemia cancer cell through inhibition the activity of Bcl-2 proteins

Abstract

BackgroundHypericum japonicum Thunb. ex Murray is widely used as an herbal medicine for the treatment of hepatitis and tumours in China. However, the molecular mechanisms of its effects are unclear. Our previous research showed that extracts of H. japonicum can induce apoptosis in leukaemia cells. We also previously systematically analysed and isolated the chemical composition of H. japonicum.MethodsThe fluorescence polarisation experiment was used to screen for inhibitors of Bcl-2 proteins which are proved as key proteins in apoptosis. The binding mode was modelled by molecular docking. We investigated the proliferation attenuating and apoptosis inducing effects of active compound on cancer cells by MTT assay and flow cytometry analysis. Activation of caspases were tested by Western blot. A broad-spectrum caspase inhibitor Z-VAD-FMK was used to investigate the caspases-dependence. In addition, co-immunoprecipitation was performed to analyse the inhibition of heterodimerization between anti-apoptotic Bcl-2 proteins with pro-apoptotic proteins. Moreover, in vivo activity was tested in a mouse xenograph tumour model.ResultJacarelhyperol A (Jac-A), a characteristic constituent of H. japonicum, was identified as a potential Bcl-2 inhibitor. Jac-A showed binding affinities to Bcl-xL, Bcl-2, and Mcl-1 with Ki values of 0.46 μM, 0.43 μM, and 1.69 μM, respectively. This is consistent with computational modelling results, which show that Jac-A presents a favorable binding mode with Bcl-xL in the BH3-binding pocket. In addition, Jac-A showed potential growth inhibitory activity in leukaemia cells with IC50 values from 1.52 to 6.92 μM and significantly induced apoptosis of K562 cells by promoting release of cytochrome c and activating the caspases. Jac-A also been proved that its effect is partly caspases-dependent and can disrupt the heterodimerization between anti-apoptotic Bcl-2 proteins with pro-apoptotic proteins. Moreover, Jac-A dose-dependently inhibited human K562 cell growth in a mouse xenograph tumour model with low toxicity.ConclusionIn this study, a characteristic constituent of H. japonicum, Jac-A, was shown to induce apoptosis in leukaemia cells by mediating the Bcl-2 proteins. Therefore, we propose a new lead compound for cancer therapy with a low toxicity, and have provided evidence for using H. japonicum as an anti-cancer herb.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-689) contains supplementary material, which is available to authorized users.

Identification of a new class of natural product MDM2 inhibitor:In vitroandin vivoanti-breast cancer activities and target validation

“…The investigated compounds, including JapA, were obtained from a natural product library established in Dr. Wei-Dong Zhang's laboratory, with their purity being >95% (confirmed by IR, ESI-MS, NMR, and HPLC/MS n ) [ 48 ]. All chemicals and solvents were of the highest analytical grade available.…”

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

“…Previous studies on this plant have revealed the presence of flavonoids, xanthonoids, chromone glycosides, phloroglucinol derivatives and lactones, and many of these secondary metabolites exhibit versatile pharmacological activities34567.…”

“…Hypericum japonicum Thunb, an annual herbaceous plant of the genus Hypericum (Hypericaceae), widely distributed in Asia, Oceania, and North America, has been historically used for the treatment of hepatitis, tumors, and gastrointestinal disorder in Chinese traditional medicine 1 2 . Previous studies on this plant have revealed the presence of flavonoids, xanthonoids, chromone glycosides, phloroglucinol derivatives and lactones, and many of these secondary metabolites exhibit versatile pharmacological activities 3 4 5 6 7 .…”

Discovery of SCY45, a Natural Small‐Molecule MDM2‐p53 Interaction Inhibitor

“…The docking method that was used is described in previous work. [4] In summary, molecular modeling was performed using Maestro 9.0. The crystal structure of an MDM2/nutlin-3a complex with a resolution of 1.6 Å (PDB code: 4HG7) was downloaded from the Protein Data Bank (PDB, http://www.pdb.org) and was prepared with the 'Protein Preparation Wizard' workflow with the default settings.…”

“…[2] Thus, PPIs are attractive molecular targets for novel therapies. [3,4] The MDM2-p53 interaction is a good example of signaling proteins for which PPIs have been targeted and small-molecule inhibitors have entered clinical trials. [5] The p53 tumor suppressor protein is a transcription factor that is responsible for maintaining genome integrity, which is related to several cellular processes, including the cell cycle, apoptosis, DNA repair, and angiogenesis.…”