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JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin

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Abstract

Purpose

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells.

Methods

The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species.

Results

We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production.

Conclusions

JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

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Acknowledgements

We sincerely thank other colleagues in our laboratory for their active help in this study. This work was supported by The National Natural Science Funds (No. 81272833) of China.

Funding

This study was funded by The National Natural Science Funds of China (Grant Number 81272833).

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Author notes

  1. Mingning Qiu and Longzhi Ke authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Urology, Guangdong Medical University, Zhanjiang, 524001, China

    Mingning Qiu, Longzhi Ke, Sai Zhang, Xin Zeng, Zesong Fang & Jianjun Liu

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  1. Mingning Qiu
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  2. Longzhi Ke
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  3. Sai Zhang
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  4. Xin Zeng
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Correspondence to Jianjun Liu.

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Qiu, M., Ke, L., Zhang, S. et al. JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin. Cancer Chemother Pharmacol 80, 275–286 (2017). https://doi.org/10.1007/s00280-017-3359-9

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