title: A reactive oxygen species activation mechanism contributes to JS-K-induced apoptosis in human bladder cancer cells.
abstract: Reactive oxygen species (ROS) and cellular oxidant stress are regulators of cancer cells. The alteration of redox status, which is induced by increased generation of ROS, results in increased vulnerability to oxidative stress. The aim of this study is to investigate the influence of O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, C13H16N6O8) on proliferation and apoptosis in bladder cancer cells and explored possible ROS-related mechanisms. Our results indicated that JS-K could suppress bladder cancer cell proliferation in a concentration- and time-dependent manner and induce apoptosis and ROS accumulation in a concentration-dependent manner. With increasing concentrations of JS-K, expression of proteins that are involved in cell apoptosis increased in a concentration-dependent manner. Additionally, the antioxidant N-acetylcysteine (NAC) reversed JS-K-induced cell apoptosis; conversely, the prooxidant oxidized glutathione (GSSG) exacerbated JS-K-induced cell apoptosis. Furthermore, we found that nitrites, which were generated from the oxidation of JS-K-released NO, induced apoptosis in bladder cancer cells to a lower extent through the ROS-related pathway. In addition, JS-K was shown to enhance the chemo-sensitivity of doxorubicin in bladder cancer cells. Taken together, the data suggest that JS-K-released NO induces bladder cancer cell apoptosis by increasing ROS levels, and nitrites resulting from oxidation of NO have a continuous apoptosis-inducing effect.
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Mingning
authors.initials: M
authors.lastname: Qiu
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Lieqian
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Tan
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Longzhi
authors.initials: L
authors.lastname: Ke
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Hege
authors.initials: H
authors.lastname: Chen
authors.affiliation: Laboratory of Urology, Guangdong Medical University, Zhanjiang 524001, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001391:Azo Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism
chemical_list: D001391:Azo Compounds; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D005978:Glutathione