A reactive oxygen species activation mechanism contributes to JS-K-induced apoptosis in human bladder cancer cells.

Mingning Qiu,Jianjun Liu,Lieqian Chen,Guobin Tan,Hege Chen,Longzhi Ke,Sai Zhang

doi:10.1038/srep15104

Mingning Qiu, Jianjun Liu + Show 5 more

Open Access

https://doi.org/10.1038/srep15104

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Journal: Scientific reports	Publication Date: Oct 13, 2015
Citations: 60	License type: CC BY 4.0

Affiliation: Guangdong Medical College

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.

Highlights

Reactive oxygen species (ROS) and cellular oxidant stress are regulators of cancer cells
We found that untreated cells grew well, whereas cells treated with JS-K for 24 h were distorted in shape, became round and underwent apoptosis (Fig. 1A)
It is widely recognized that reactive oxygen species (ROS) play critical roles in causing cell damage and physiological dysfunction and that the accumulation of ROS is involved in multiple events in cancer, including inflammation, cell cycle progression, apoptosis, migration, and invasion[13,14]

Summary

Introduction

Reactive oxygen species (ROS) and cellular oxidant stress are regulators of cancer cells. 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. 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. As a NO-donor prodrug, JS-K is reported to inhibit cancer cell proliferation and induce apoptosis[9], and treatment with JS-K results in oxidative/nitrosative stress www.nature.com/scientificreports/. JS-K promoted ROS levels, increased cytotoxicity and caspase-3/7 activity, and activated caspase-9 protein in bladder cancer cells in a concentration-dependent manner; these effects, in turn, induced cellular apoptosis. JS-K-released NO was oxidized into nitrites, which subsequently induced apoptosis in bladder cancer cells through an ROS-related pathway

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