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.
Keywords: Apoptosis; Bladder cancer; Cell cycle; Combination; UA17.
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