Bladder cancer is the fourth most common type of cancer in men (ninth in women) in the United States. Cisplatin is an effective agent against the most common subtype, urothelial carcinoma. However, the development of chemotherapy resistance is a severe clinical problem for the successful treatment of this and other cancers. A better understanding of the cellular and molecular events in response to cisplatin treatment and the development of resistance are critical to improve the therapeutic options for patients. Here, we report that expression of the CCAAT/enhancer binding protein delta (CEBPD, C/EBPδ, NF-IL6β) is induced by cisplatin in the human bladder urothelial carcinoma NTUB1 cell line and is specifically elevated in a cisplatin resistant subline. Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. Several reports have implicated CEBPD as a tumor suppressor gene. This study reveals a novel role for CEBPD in conferring drug resistance, suggesting that it can also be pro-oncogenic. Furthermore, our data suggest that SOD inhibitors, which are already used as anti-angiogenic agents, may be suitable for combinatorial chemotherapy to prevent or treat cisplatin resistance in bladder and possibly other cancers.
A known triterpenoid, β-amyrin (1), and a known and a new phloroglucinol, cohulupone (2) and garcinielliptone P (3), were isolated from the pericarp and heartwood and seed of Garcinia subelliptica, respectively. A new xanthonolignoid, hyperielliptone HF (4), was isolated from the heartwood of Hypericum geminiflorum. The new compounds were established by analysis of their spectroscopic data. Compounds 1-3 showed an inhibitory effect on xanthine oxidase (XO). Treatment of NTUB1, a human bladder cancer cell, with 1 or 1 cotreated with cisplatin for 24 h resulted in a decreased viability of cells. Exposure of NTUB1 to 1 or 1 cotreated with cisplatin for 24 h significantly increased the level of production of reactive oxygen species (ROS). Flow cytometric analysis indicated that treatment of NTUB1 with 1 or 1 cotreated with cisplatin led to the cell cycle arrest, accompanied by an increase in the extent of apoptotic cell death in 1 or 1 combined with cisplatin-treated NTUB1 after 24 h. These data suggested that the presentation of cell cycle arrest and apoptosis in 1 or 1 combined with cisplatin-treated NTUB1 for 24 h was mediated through an increased amount of ROS in cells exposed to 1 or 1 cotreated with cisplatin.
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