The synthesis and anti-tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors.

A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 µM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.

MiR-422a in gastric cancer cells directly targets CDC40 and modulates cell proliferation.

MicroRNAs have been shown to be involved in a variety of different human cancers, including gastric cancer, functioning as post-transcriptional regulators of oncogenes or tumor suppressors. This study aimed to clarify the role of miR-422a in gastric cancer and further elucidate the pathogenesis thereof. To this end, miR-422a expression was initially determined in gastric cancer tissues and cells. Our results showed decreased miR-422a and increased cell division cycle 40 (CDC40) expression in gastric cancer. Dual-luciferase reporter assay further confirmed that miR-422a targeted CDC40. Altogether, this study showed that miR-422a downregulated CDC40, thereby affecting cell cycle progression. Moreover, restoration of miR-422a inhibited gastric cancer cell proliferation. In summary, this study has been the first to show that miR-422a was associated with CDC40 levels in human gastric cancer cells and that disease development may be attributed to CDC40.

[Research advances on anti-ANGPT2 antibody in acute myeloid leukemia].

Angiopoietin2( ANGPT2 ) plays an important role in tumor angiopoiesis. ANGPT2 antagonises ANGPT1 resulting in an effect on the stability of blood vessels, which promotes tumor growth, invasion, proliferation as well as relating to tumor vascular density. A lot of researches published papers about anti-ANGPT2 for the treatment of tumor, and have made some progresses. In this review, the role of ANGPT2 in the pathogenesis of acute myelogenous leukemia (AML), including its effects on proliferation of leukemia cells, bone marrow angiopoiesis, tumor invasion and metastasis are briefly summarised in order to provide the basis for targeted ANGPT2 in treatment of AML.

A unique MUC1-2-VNTR DNA vaccine suppresses tumor growth and prolongs survival in a murine multiple myeloma model.

Multiple myeloma (MM) is a clonal B-cell malignancy charactered by the aberrant proliferation of malignant plasma cells in the bone marrow. MM is still an incurable malignancy. In this regard, novel treatments are urgently required. MUC1 (mucin 1), a type І transmembrane protein, is overexpressed and aberrantly glycosylated in many carcinomas particularly in MM resulting in an antigenically distinct molecule and may be a potential target for specific immunotherapy. In this study, we first designed a unique DNA vaccine, termed MUC1-2-VNTR (various number tandem repeats) to investigate whether the vaccine could specifically suppress tumor growth in a murine multiple myloma model. Our results showed that the constructed DNA vaccine pcDNA3.1-VNTR elicited both humoral and cellular tumor-specific immune responses in the MM mouse model leading to delay in tumor growth and prolonged survival of the mice. Consequently, our study indicates that this DNA vaccine shows promise to be used as a novel strategy for the treatment of MM.

[Construction of eukaryotic expressing vector of multiple myeloma mucin-1 and its expression in COS-7 cells in vitro].

In order to construct an eukaryotic expression vector for gene of multiple myeloma mucin1 (muc1-2vntr) gene and to express it in COS-7 cells in vitro, so to provide the basic material for further research of multiple myeloma DNA vaccine. muc1-2vntr coding gene was used as a research gene and a KOZAK sequence was inserted before the gene Hind III and XbaI restriction sites were inserted before and after the coding gene. Then the whole sequence was synthesized and inserted into pcDNA3.1/myc-his B vector, and the resulted recombinant vector was transformed into E.coil competent cells to get an engineering strain, the recombinant plasmid pcDNA3.1-2vntr/myc-his B identified by restriction analysis and DNA sequencing were transfected into COS-7 cells by liposome-mediated gene transfer method. Finally, fluorescent microscopy was used to assess GFP expression and Western blot analysis using muc1 monoclonal antibody was used to recognize vntr, confirming the expression of vntr. The results showed that the full length of synthesized muc1-2vntr gene, as expected, was 140 bp. Both restriction analysis and DNA sequencing demonstrated that pcDNA3.1-2vntr/myc-his B included the whole translation frame region and muc1-2vntr gene. Furthermore, the fluorescence microscopy proved that the recombinant plasmid had been successfully transfected into COS-7 cells. The expression of mucin-1 protein was observed both in the transfected cell and the cell supernatant by Western blot. It is concluded that the pcDNA3.1-2vntr/myc-his B has been successfully constructed and expressed in COS-7 cells in vitro, which provides the basic material for further researches of mucin-1 function and possible multiple myloma DNA vaccine.

[Synergism and attenuation effects of taurine on cyclophosphamide].

BACKGROUND AND OBJECTIVE: Cyclophosphamide (CTX) is a commonly used clinical antitumor drug with severe side effects. Therefore, it is important to find ancillary drugs which have synergism and attenuation effects on CTX. This study was to investigate the synergism and attenuation effects of taurine (Tau) on CTX via different administration methods. METHODS: S180-bearing mice were given Tau combined with CTX via either intravenous injection or intragastric administration. The tumor inhibition rate, the count of bone marrow nucleate cells and white blood cells, the spleen index, the thymus index, lymphocyte proliferation and the phagocytic activity of peritoneal macrophage were calculated. RESULTS: The tumor inhibition rates of intravenous administration of 40 mg * kg(-1), 80 mg * kg(-1),160 mg * kg(-1) Tau combined with CTX (20 mg * kg(-1)) were 66.4%, 74.5% and 84.6%, while those of intragastric administration of 160 mg * kg(-1), 320 mg * kg(-1), 640 mg * kg(-1) Tau with CTX (20 mg * kg(-1)) were 60.1%, 69.7% and 81.2%, all of which were higher than that of CTX administration (20 mg * kg(-1)) alone (55.8%). Compared to the CTX group, the count of bone marrow nucleate cells and the white blood cells, the spleen index, the thymus index, lymphocyte proliferation and the phagocytic activity of peritoneal macrophage were elevated in all Tau and CTX combination groups. CONCLUSION: Tau has synergism and attenuation effects on CTX via both intravenous and intragastric administration.

[Expression of oncogene C-jun in the cells of rat nasal mucosa and relevance with rhinorrhea].

OBJECTIVE: To study the expression of oncogene C-jun in rat nasal mucosa with allergic rhinitis and the relevance with rhinorrhea. METHOD: By using EA to make animal model of allergic rhinitis successfully; the amount of rhinorrhea was calculated at 30 min. 4 h, 8 h. Immunohistochemical technique, computer image analysis technique and histologic examination were used to investigated the expression of C-jun in rat nasal mucosa at the same time. The relevance between them was used explored. RESULT: There was a lot of C-jun protein at 30 min. The difference of C-jun between 30 min group and control group was significant (P < 0.01) and the relevant coefficient was r = 0.784 (P < 0.05). The C-jun protein decreased at 4 h, but there was still significant difference (P < 0.05) and r = 0.626 (P < 0.05). The C-jun was as same as control group at 8 h, There was no difference between them. CONCLUSION: The expression of oncogene C-jun in inflammatory cells may be a marker in early stage of activation of inflammatory cells, and related to the producing and secreting of cytokines and inflammatory mediators in inflammatory cells of allergic rhinitis.