Investigation of the impact of Globo-H expression on the progression of gastric cancer.

Globo-H (GH), a globo-series glycosphingolipid antigen that is synthesized by key enzymes ß1,3-galactosyltransferase V (ß3GalT5), fucosyltransferase (FUT) 1 and 2, is highly expressed on a variety of epithelial cancers rendering it a promising target for cancer immunotherapy. GH-targeting antibody-drug conjugate has been demonstrated an excellent tumor growth inhibition potency in animal models across multiple cancer types including Gastric cancer (GC). This study aims to further investigate the GH roles in GC. Significant correlations were observed between high mRNA expression of GH-synthetic key enzymes and worse overall survival (OS)/post-progression survival for GC patients based on the data from "Kaplan-Meier plotter" database (n=498). The level of GH expression was evaluated in clinical adenocarcinoma samples from 105 patients with GC by immunohistochemistry based on H-score. GH expression (H score ≥ 20; 33.3%) was significantly associated with a poor disease specific survival (DSS) and invasiveness in all samples with P=0.029 and P=0.013, respectively. In addition, it is also associated with shorter DSS and OS in poorly differentiated tumors with P=0.033 and P=0.045, respectively. Particularly, with patients ≥ 65 years of age, GH expression is also significantly associated with the stages (P=0.023), differentiation grade (P=0.038), and invasiveness (P=0.026) of the cancer. Sorted GC NCI-N87 cells with high level of endogenous GH showed higher proliferative activity compared with low-GH-expressing cells based on PCNA expression. Micro-western array analysis on high-GH-expressing GC cells indicated an upregulation in HER2-related signaling proteins including phospho-AKT/P38/JNK and Cyclin D1/Cyclin E1 proteins. Moreover, GH level was shown to be correlated with expression of total HER2 and caveolin-1 in GC cells. Immunoprecipitation study suggested that there are potential interactions among GH, caveolin-1, and HER2. In conclusions, GH level was significantly associated with the worse survival and disease progression in GC patients, especially in older patients. Enhanced cell proliferation activity through interactions among GH, HER2, and caveolin-1 interactions may contribute to GH induced tumor promotion signaling in GC. GH-targeting therapy may be a viable option for the treatment of GC patients.

Melittin suppresses epithelial-mesenchymal transition and metastasis in human gastric cancer AGS cells via regulating Wnt/BMP associated pathway.

Gastric cancer has a poor prognosis; once cancer has metastasized, it can easily lead to patient death. Melittin is one of the major components extracted from the bee venom. It has been shown that melittin emerges antitumor activities against many human cancer cell lines. Our results indicated that melittin at 0.2-0.5 µm significantly reduced total cell viability in human gastric cancer AGS cells. At low concentrations (0.05-0.15 µm), melittin displayed antimetastasis effects and inhibited cell adhesion and colony formation. Besides, it inhibited cell motility and suppressed cell migration and invasion. Melittin inhibited the activities of MMP-2 and MMP-9 and the integrity of cell membrane in AGS cells. Furthermore, Western blotting results showed that melittin decreased the protein expressions of Wnt/BMP and MMP-2 signaling pathways. Based on these observations, melittin inhibited cell migration and invasion of AGS cells through multiple signaling pathways. It may be used to treat metastasized gastric cancers in the future.

Demethoxycurcumin Inhibits In Vivo Growth of Xenograft Tumors of Human Cervical Cancer Cells.

BACKGROUND/AIM: Demethoxycurcumin (DMC), a derivate of curcumin from natural plants, exerts antitumor effects on various human cancer cells in vitro and in vivo. Nevertheless, no reports have disclosed whether DMC can affect the growth of human cervical cancer cells in vivo. Therefore we investigated the antitumor effects of DMC on a HeLa cell xenograft model in nude mice in this study. MATERIALS AND METHODS: Twenty-four nude mice were subcutaneously injected with HeLa cells. All mice were randomly divided into control, low-dose DMC (30 mg/kg), and high-dose DMC (50 mg/kg) groups and individual mice were treated intraperitoneally accordingly every 2 days. RESULTS: DMC significantly reduced tumor weights and volumes of HeLa cell xenografts in mice, indicating the suppression of growth of xenograft tumors. CONCLUSION: These effects and findings might provide evidence for investigating the potential use of DMC as an anti-cervical cancer drug in the future.

4-Ethoxybenzoic acid inhibits Staphylococcus aureus biofilm formation and potentiates biofilm sensitivity to vancomycin.

The adverse health effects of Staphylococcus aureus biofilm infections coupled with an increased global prevalence of antibiotic resistance highlight the need for novel anti-pathogenic, anti-biofilm compounds. The authors recently determined that ethyl-4-ethoxybenzoic acid (EEB) had anti-pathogenic, anti-biofilm activity. Based on this finding, a structure-activity analysis was undertaken to identify more effective compounds. Microtitre crystal violet assays followed by plate counts were conducted to measure the dose-dependent anti-biofilm and antimicrobial activities of 13 phenolic compounds related to EEB. By displaying these characteristics on a two-component plot, 4-ethoxybenzoic acid (4EB) and methyl gallate were identified as two anti-pathogenic, anti-biofilm compounds of interest. To characterize their mechanisms of activity, their effects on cell hydrophobicity, hemolysis activity, membrane integrity, extracellular polymeric substance production and vancomycin sensitivity were examined. Both 4EB and methyl gallate inhibited up to 87% of biofilm formation with minimal impact on the viability of stationary-phase cells or bacterial growth. Combination treatments of 4EB and vancomycin decreased the viability of biofilm-dwelling cells by up to 85% compared with vancomycin alone, indicating a synergistic effect. Methyl gallate did not potentiate vancomycin. 4EB decreased the percentage of hydrophobic cells in culture from 78% to 49%, indicating that 4EB may prevent biofilm formation by altering cell membrane hydrophobicity. These findings suggest that 4EB has potential as an anti-pathogenic, anti-biofilm agent for the prevention of S. aureus biofilms, or as a treatment for established biofilms when combined with antibiotics.

Maslinic Acid Enhances Immune Responses in Leukemic Mice Through Macrophage Phagocytosis and Natural Killer Cell Activities In Vivo.

BACKGROUND/AIM: Maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, has been shown to reduce cancer cell number through induction of autophagy and apoptosis in many human cancer cells including human leukemia HL-60 cells. In the present study, we investigated whether or not MA affects immune responses in a leukemia mouse model. MATERIALS AND METHODS: WEHI-3 cells were intraperitonealIy (i.p.) injected into normal BALB/c mice to develop leukemia. Mice were then treated by i.p. injection with MA at different doses (0, 8, 16 and 32 mg/kg) for 2 weeks. After treatment, all animals were weighed and blood, liver and spleen tissues were weighed. Blood or spleen both were used for determination of cell markers or phagocytosis, natural killer (NK) cell activities and T- and B-cell proliferation, respectively, by using a flow cytometric assay. RESULTS: MA did not significantly affect body, liver, and spleen weights. However, MA increased markers of T-cells (at 16 mg/kg treatment) and monocytes (at 32 mg/kg treatment), but reduced B-cell markers (at 8 mg/kg treatment); MA did not significantly affect cell marker of macrophages. Furthermore, MA increased phagocytosis by macrophages from peripheral blood mononuclear cells and peritoneal cavity at 32 mg/kg treatment and increased NK cell activity at target cell:splenocyte ratio of 25:1 but did not affect B- and T-cell proliferation. CONCLUSION: MA increased immune responses by enhancing macrophage phagocytosis and NK cell activities in leukemic mice.