Improvement of resistance to oxaliplatin by vorinostat in human colorectal cancer cells through inhibition of Nrf2 nuclear translocation.

Vorinostat (suberoylanilide hydroxamic acid: SAHA), a histone deacetylase inhibitor, has potential benefit of improving the resistance to conventional other anti-cancer drugs. This study was aimed to clarify whether SAHA improves the resistance to oxaliplatin (L-OHP), a platinum-based anticancer drug using L-OHP-resistant HCT116 cells (HCT116/OxR), established from colorectal cancer (CRC) cell line HCT116. HCT116/OxR cells showed cross-resistance to other platinum-based drugs. Pre-treatment with SAHA improved the sensitivity of both L-OHP and its metabolite in HCT116/OxR cells, but not in parental HCT116 cells. However, pre-treatment with SAHA did not affect the sensitivity of other platinum-based drugs. These results indicated that SAHA specifically improved the sensitivity of L-OHP in HCT116/OxR cells. Focusing on NF-E2 p45-related factor 2-Kelch-like ECH-associated protein 1 pathway (Nrf2-Keap1) pathway, which is activated by oxidative stress such as the treatment with anti-cancer drugs, mechanisms behind these observations were elucidated. In HCT116/OxR cells transfected with Nrf2 siRNA, the improving effects on L-OHP resistance by SAHA were abolished, suggesting that Nrf2-Keap1 pathway was involved in L-OHP-resistance. In addition, L-OHP metabolite significantly induced the expression of the nuclear protein Nrf2 and its target gene mRNA expression in HCT116/OxR cells. Pre-treatment with SAHA suppressed these changes observed in HCT116/OxR cells. In conclusion, this study demonstrated that SAHA improved L-OHP resistance by inhibiting Nrf2-Keap1 activation via Nrf2 nuclear translocation by L-OHP metabolite.

[Thoracoscopic Plication for Congenital Diaphragmatic Eventration in an Adult].

Thoracoscopic plication for congenital diaphragmatic eventration in an adult. Diaphragmatic eventration is known to be abnormal elevation of diaphragm and congenital causes are due to abnormal diaphragm muscle development. Here we report surgical treatment of congenital diaphragmatic eventration. A 45-year-old woman who complained of cough was admitted to our hospital. She had history of cough and was diagnosed as diaphragmatic eventration in childhood. Chest X-ray showed elevated left hemidiaphragm with a bowel gas underneath. Under the diagnosis of congenital eventration of left hemidiaphragm, plication of the left diaphragm by video-assisted thoracoscopic surgery (VATS) was performed. One month after surgery, severe cough disappeared completely.