A nitric oxide-releasing prodrug promotes apoptosis in human renal carcinoma cells: Involvement of reactive oxygen species

Jindong Xie,Weiwei Yue,Lieqian Chen,Chunxiao Liu,Dongqiang Huang,Jingyu Chen

doi:10.1515/chem-2020-0075

Jindong Xie, Weiwei Yue + Show 4 more

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https://doi.org/10.1515/chem-2020-0075

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Abstract

Abstract Background JS-K is a nitric oxide (NO)-releasing prodrug of the O2-arylated diazeniumdiolate group that shows pronounced cytotoxicity and antitumor properties in numerous cancer models, including in vitro as well as in vivo. Reactive oxygen species (ROS) induce carcinogenesis by altering the redox status, causing increment in vulnerability to oxidative stress. Material and methods To determine the effect of JS-K, a glutathione S-transferase (GST)-activated NO-donor prodrug, on the induction of ROS accumulation, proliferation, and apoptosis in human renal carcinoma cells, we measured the changes of cell proliferation, apoptosis, ROS growth, and initiation of the mitochondrial signaling pathway before and after JS-K treatment. Results In vitro, dose- and time-dependent development of renal carcinoma cells were controlled for JS-K, and JS-K also triggered ROS aggregation and cell apoptosis. Treatment with JS-K induces the levels of pro-apoptotic proteins (Bak and Bax) and decrease the number of anti-apoptotic protein (Bcl-2). In fact, JS-K-induced apoptosis was reversed by the antioxidant N-acetylcysteine, and oxidized glutathione, a pro-oxidant, improved JS-K-induced apoptosis. Finally, we demonstrated that in renal carcinoma cells, JS-K improved the chemosensitivity of doxorubicin. Conclusion Our data indicate that JS-K-released NO induce apoptosis of renal carcinoma cells by increasing ROS levels.

Highlights

Renal cell carcinoma (RCC) is a prevalent urogenital system malignant tumor with an incidence of approximately 5–10 per 100,000, representing 2–3% of all adult tumors [1], with one of the highest incidences of urological malignancies
We found significantly increased levels of Reactive oxygen species (ROS)/responsive nitrogen types (RNS) along with the increased apoptosis and inhibition of cell proliferation in two renal carcinoma cell lines following the treatment with JS-K
We demonstrated that the GSH level was significantly reduced by JS-K but increased the GSSG production in renal carcinoma cells, which lead to a reduction in the GSH/GSSG ratio

Summary

Introduction

Renal cell carcinoma (RCC) is a prevalent urogenital system malignant tumor with an incidence of approximately 5–10 per 100,000, representing 2–3% of all adult tumors [1], with one of the highest incidences of urological malignancies. According to the prediction by the American Cancer Society of the United States, almost 73,800 new cases of RCC and nearly 14,700 associated demises were reported in 2019. Various methods of treating RCC, for instance, conventional immunotherapy, targeted therapy, and radical surveillance, are currently available. Around 40% of patients, regrettably, are immune to radiation therapy and conventional chemotherapy. Such individuals may suffer systemic recurrence, resulting in high toxicity and poor treatment response [3], and a severe effect on disease-related death, with a very low 5-year survival rate (only 10–12%) [4]. More studies on the mechanisms involved in the growth and advancement of RCC are need to identify new therapeutic targets

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