A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC50 value of MHY4381 was lower in DU145 cells (IC50=0.31 μM) than in LNCaP (IC50=0.85 μM) and PC-3 cells (IC50=5.23 μM). In addition, the IC50 values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 muM) than in DU145 cells (IC50=1.10 muM) and PC3 cells (IC50=5.60 muM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.

Expression of CD44 in endometrial stromal cells from women with and without endometriosis and its effect on the adherence to peritoneal mesothelial cells

OBJECTIVE: This study was performed to compare the expression of CD44 in endometrial stromal cells (ESCs) of women with and without endometriosis and to evaluate the role of CD44 in the adherence of ESCs to peritoneal mesothelial cells (PMCs). METHODS: A PMC adherence assay was performed to evaluate the adherence of ESCs to PMCs in women with and without endometriosis. The expression of CD44 mRNA was measured by reverse transcription-polymerase chain reaction. CD44 protein was evaluated by Western blot analysis. RESULTS: There were no significant differences in the expression of CD44 mRNA and protein in ESCs or in the binding of ESCs to PMCs between patients with endometriosis and controls. Although the expression of CD44 protein was decreased in both women with endometriosis and controls after anti-CD44 antibody treatment, there was no effect on binding of ESCs to PMCs. Treatment of ESCs with peritoneal fluid from endometriosis patients resulted in a significant increase in binding of ESCs to PMCs compared to untreated ESCs in the endometriosis group. CONCLUSION: This study demonstrates that the expression of CD44 protein in ESCs from women with endometriosis might not be directly associated with adherence to PMCs.

Osteogenic Induction of Periosteum-Derived Stem Cells Transplanted into Rabbit Long-Bone Defects / 대한정형외과학회잡지

PURPOSE: To determine if stem cells transplanted directly into a bone defect of rabbit tibias have osteogenic induction potential. MATERIALS AND METHODS: Immature white New Zealand rabbits underwent tibial osteotomies, and were divided into three groups according to the implant material used: stem cells embedded in agar (group 1); agar alone (group 2); nothing (group 3). For all rabbits, radiographs were taken weekly for 8 weeks, and histological studies of the newly formed-bone were performed. CM-Dil was used to label the stem cells prior to transplantation to ascertain whether or not the newly formed bone was derived from the transplanted stem cells. RESULTS: Fibroblasts and osteoblasts (osteoid matrix-forming cells) derived from the stem cells were identified by electron microscopy. Interspersed enchondral ossification (probably induced by osteogenic cells from the remaining periosteum and marrow) and pure osteoids (created directly from the osteoblasts originating from the transplanted stem cells) were identified. Fluorescent-labeled cells were conspicuous in the new bones until 6 weeks after surgery, which indicates that the new bones were induced by the stem cells. CONCLUSION: The osteogenic induction potential of the undifferentiated stem cell has promise for therapeutic application, which may be used for the treatment of bone defects in the future.

A Study for Pressure-Flow Relationship and Oxygenation in the Denervated Canine Liver / 대한마취과학회지

BACKGROUND: Various pressor agents are used to raise systemic vascular resistance (SVR) during liver transplantation. The aim of this study was to investigate the effect of liver denervation on hepatic hemodynamic responses to vasopressors. METHODS: This study was conducted in eight anesthetized dogs randomly assigned in to 4 groups [epinephrine-Low dose (L): 0.05 microgram/kg/min, epinephrine-High dose (H): 0.5 microgram/kg/min, ephedrine (D): 0.2 mg/kg, phenylephrine (P): 80 microgram/min]. One hour after surgical denervation of the liver, cardiac output, blood gases and hepatic blood flow were measured before and after administration of vasopressors with an electromagnetic flow meter. Oxygen consumption rate (hepatic artery plus portal vein oxygen delivery-hepatic vein oxygen delivery) was calculated. The Wilcoxon signed rank test and Kruskal-Wallis test were used for statistical analysis; The level of significance was assumed at the P < 0.05 level. Results are expressed as mean +/- SE. RESULTS: The resulting hemodynamic values were not significantly different between groups except for hepatic vascular resistance in the P group. Hepatic blood flow decreased significantly in the P and H groups, whereas it increased significantly in the L group. Hepatic oxygen consumption and Base Excess in hepatic venous blood after vasopressors were not significantly different between groups. These results mean there were no significant differences in hepatic oxygenation between groups. CONCLUSIONS: Various pressor agents can be used to raise SVR without jeopardizing hepatic oxygenation. However, phenylephrine and high dose of epinephrine are not recommended after liver transplantation because decreased hepatic blood flow might affect the intracellular oxygen environment adversely.