|Title:||Anti-cancer effects of ursane triterpenoid as a single agent and in combination with cisplatin in bladder cancer||Authors:||Lin K.-W.
|Keywords:||Apoptosis; Bladder cancer; Cell cycle; Combination; UA17||Issue Date:||2014||Publisher:||Elsevier||Journal Volume:||740||Start page/Pages:||742-751||Source:||European Journal of Pharmacology||Abstract:||
Ursolic acid and most of its derivatives are cytotoxic to bladder cancer cells. An ursolic acid derivative, isopropyl 3β-hydroxyurs-12-en-28-oat (UA17), previously reported that it exhibited potent cytotoxicity against bladder cancer cells, NTUB1 cells. In this study, we further investigated the underlying mechanism of UA17 and evaluated its potential clinical use. UA17 may exert the onset of a p53-mediated p38 MAPK activation to up-regulate GADD153. GADD153, in turn, down-regulated Bcl-2 protein to cause mitochondrial membrane potential loss and apoptosis through intracellular ROS generation. In addition, UA17 markedly decreased the levels of cyclins (D1 and E), cyclin-dependent kinases (CDK2 and CDK4), and caused increase of p21 and p27 levels. To assess the suitability of UA17 as a chemotherapeutic agent against NTUB1 cells, its cytotoxic effects have been further evaluated in the combination with cisplatin. The addition of UA17 to cisplatin induces possibly additive cell growth inhibition which correlated to the accumulation of S phase cells and a corresponding decrease in accumulation of G1 phase cells, accompanied an increased accumulation of sub-G1 phase cells. Furthermore, UA17/cisplatin combination exhibited increase of p21, cyclin E, and p-p53 level, and decrease of p27 and cyclin D1 proteins, and slightly diminishing the level of CDK2. P-p38 up-regulation induced by UA17/cisplatin combination through generation of ROS and Bcl-2 down-regulation induced by UA17/cisplatin combination increased cell death. Finally, the antitumorigenic effects of UA17 or UA17/cisplatin combination were further supported by their inhibition on growth of bladder tumor cells in a therapeutic murine MBT-2 bladder tumor model. ? 2014 Elsevier B.V. All rights reserved.
|ISSN:||0014-2999||DOI:||10.1016/j.ejphar.2014.05.051||SDG/Keyword:||cisplatin; cyclin D1; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin E; growth arrest and DNA damage inducible protein 153; isopropyl 3beta hydroxyurs 12 en 28 oat; mitogen activated protein kinase p38; protein bcl 2; protein p21; protein p27; protein p53; reactive oxygen metabolite; unclassified drug; ursolic acid derivative; antineoplastic agent; cell cycle protein; cisplatin; Ddit3 protein, mouse; growth arrest and DNA damage inducible protein 153; isopropyl 3-hydroxyurs-12-en-28-oate; protein p53; reactive oxygen metabolite; triterpene; animal cell; animal experiment; animal model; antiproliferative activity; apoptosis; Article; bladder cancer; bladder cancer cell line; cancer inhibition; controlled study; dose response; drug cytotoxicity; drug potentiation; drug structure; G1 phase cell cycle checkpoint; human; human cell; mitochondrial membrane potential; mouse; nonhuman; survival rate; tumor xenograft; upregulation; animal; C3H mouse; cell cycle; drug effects; metabolism; pathology; tumor cell line; tumor volume; Urinary Bladder Neoplasms; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cisplatin; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C3H; Reactive Oxygen Species; Transcription Factor CHOP; Triterpenes; Tumor Burden; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms
|Appears in Collections:||醫學系|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.