Bromodomain‐containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI‐2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4‐difluoro‐1‐methyl‐N,6‐diphenyl‐5,6‐dihydro‐4H‐pyrimido[4,5‐b] [1,2,4] triazolo[4,3‐d] [1,4] diazepine‐8‐amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4‐BD1 (IC50 value of 0.42 μM) in the BRD4‐BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4‐11 cells (IC50 value of 0.51 μM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4‐11 leukemia cells effectively, and downregulated the expression of c‐Myc in a dose‐dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.
BackgroundConsidering the narrow immune response spectrum of a single epitope, and the nanoparticles (NPs) as a novel adjuvant can achieve efficient delivery of antigenic peptides safely, a nano-system (denoted as DSPE-PEG-Man@EM-NPs) based on cathepsin B-responsive antigenic peptides was designed and synthesized.MethodsHighly affinitive antigenic peptides were delivered by self-assembled NPs, and targeted erythrocyte membranes acted as a peptide carrier to improve antigenic peptides presentation and to strengthen cytotoxic T-cells reaction. Cathepsin B coupling could release antigenic peptides rapidly in dendritic cells.ResultsEvaluations showed that DSPE-PEG-Man@EM-NPs had obvious inhibitory effects towards both MCF-7 and MDA-MB-231 human breast cancer cell lines.ConclusionOverall, this strategy provides a novel strategy for boosting cytotoxic T lymphocytes response, thereby expanding the adaptation range of tumor antigenic peptides and improving the therapeutic effect of tumor immunotherapy with nanomedicine.
Vaccines based on tumour‐specific antigens are a promising approach for immunotherapy. However, the clinical efficacy of tumour‐specific antigens is still challenging. Twelve conjugates with self‐assembly properties were designed and synthesized using MAGE‐A1 peptide and TLR2 agonist, combined with different covalent bonds. All the developed conjugates formed spherical nanoparticles with a diameter of approximately 150 nm, and enhanced the efficacy of the peptide vaccines with the better targeting of lymph nodes. All the conjugates could well bind to serum albumin and improve the plasma stability of the individual antigenic peptides. In particular, conjugate 6 (N‐Ac PamCS‐M‐6) had a more significant ability to promote dendritic cell maturation, CD8+ T cell activation, and subsequent killing of tumour cells, with an in vivo tumour inhibition rate of 70 ± 2.9%. The interaction between specific response and the different conjugation modes was further explored, thereby providing a fundamental basis for novel immune anti‐tumour molecular platforms.
BackgroundLeukaemia is a malignant leukocyte disorder with a high fatality rate, and current treatments for this disease are unsatisfactory. Therefore, new therapeutic strategies for leukaemia must be developed. Malaria parasite infection has been shown to be effective at combating certain neoplasms in animal experiments. This study is to demonstrate the anti-leukaemia activity of malaria parasite Plasmodium yoelii (P. yoelii) infection,.MethodsIn this study, the proportion of CD3, CD19, CD11b and Mac-3 cells was analysed by flow cytometry; the levels of IFN-γ and TNF-α in individual serum samples were measured by enzyme-linked immunosorbent assay, and the phagocytic activity of macrophages and natural killer (NK) cell activity were measured by flow cytometry.ResultsWe found that P. yoelii infection significantly attenuated the growth of WEHI-3 cells in mice. In addition, tumor cell infiltration into the murine liver and spleen was markedly reduced. We also demonstrated that malaria parasite infection elicited anti-leukaemia activity by promoting immune responses, including increasing the surface markers of T cells (CD3) and B cells (CD19); decreasing the surface markers of monocytes (CD11b) and macrophages (Mac-3); inducing the secretion of IFN-γ and TNF-α; and increasing NK cell and macrophage activity.ConclusionsMalaria parasite infection significantly decreases the number of myeloblasts and inhibits neoplasm proliferation in mice. In addition, malaria parasite infection inhibits murine leukaemia by promoting immune responses.Electronic supplementary materialThe online version of this article (10.1186/s40249-018-0433-4) contains supplementary material, which is available to authorized users.
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