HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells.

HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors.

Mortality and cause of death in patients with tracheostomy: Longitudinal follow-up study using a national sample cohort.

BACKGROUND: The purpose of this study was to evaluate the long-term mortality and cause of death in patients with tracheostomy. METHODS: Data from the Korean National Health Insurance Service-Health Screening Cohort were collected from 2002 to 2013. A total of 2394 tracheostomy participants and 9536 control participants were included in this study. The crude and adjusted hazard ratios (HRs) for tracheostomy-associated mortality were analyzed. Subgroup analysis according to age and cause of death was analyzed. RESULTS: The tracheostomy group showed a significantly higher rate of death (69.1%) than the nontracheostomy group (13.3%). The adjusted HR for mortality was 13.5 in the tracheostomy group. The most common cause of death after tracheostomy was a circulatory disease, followed by neoplasm, respiratory disease, and trauma. CONCLUSIONS: Patients with tracheostomy had a significantly increased long-term mortality rate compared with patients with nontracheostomy. The circulatory disease was the most common cause of death following tracheostomy.

Eupatilin downregulates phorbol 12-myristate 13-acetate-induced MUC5AC expression via inhibition of p38/ERK/JNK MAPKs signal pathway in human airway epithelial cells.

Chronic inflammatory airway diseases, such as chronic rhinosinusitis, chronic obstructive pulmonary disease, and asthma, are associated with excessive mucus production. Hence, the regulation of mucus production is important for the treatment of upper and lower airway diseases. Eupatilin is a pharmacologically active ingredient obtained from Artemisia asiatica Nakai (Asteraceae) and exerts potent anti-inflammatory, anti-allergic, and anti-tumor activities. In the present study, we investigated the effect of eupatilin on phorbol 12-myristate 13-acetate (PMA)-induced MUC5AC and MUC5B expression in human airway epithelial cells. We found that eupatilin treatment significantly inhibited PMA-induced mucus secretion in PAS staining. In addition, qRT-PCR results showed that eupatilin dose-dependently decreased the mRNA expression of MUC5AC in human airway epithelial cells. Western blot and immunofluorescence assay also showed that PMA-induced protein expression of MUC5AC was inhibited by eupatilin treatment. Finally, we investigated MAPKs activity after stimulation with PMA using western blot analysis in human airway epithelial cells. The results showed that eupatilin downregulated the levels of phosphorylated p38, ERK, and JNK. In summary, the anti-inflammatory activities of eupatilin, characterized as the suppression of MUC5AC expression and secretion in human airway epithelial cells, were found to be associated with the inhibition of p38/ERK/JNK MAPKs signaling pathway of MUC5AC secretion.