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The Xc− inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism

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Abstract

Purpose

Traditional treatment regimens for advanced prostate cancer, especially castration-resistant prostate cancer, result in low survival times with severe side effects. Therefore, new treatment options are required. Vitamin C (VC) has been identified as a promising anti-cancer agent of which the effects depend on the accumulation of H2O2 that is produced through autoxidation. Sulfasalazine (SAS), a cystine transporter (Xc−) inhibitor, is known to suppress cellular glutathione (GSH) biosynthesis. Here, we hypothesized that targeting the Xc− transporter via SAS may improve the anti-cancer activity of VC through regulating GSH biosynthesis, which in turn may result in the accumulation of reactive oxygen species (ROS).

Methods

The anti-cancer effect of VC and/or SAS on prostate cancer cells was assessed using WST-8, colony formation and annexin V-FITC/PI FACS assays. Changes in cellular ROS and GSH levels were determined to verify our hypothesis. Finally, BALB/c nude mice bearing prostate cancer xenografts were used to assess the anti-cancer effects of single or combined VC and SAS therapies.

Results

We found that SAS could potentiate the short- and long-term cytotoxicity of VC in prostate cancer cells. We also found that the synergistic effect of SAS and VC led to significant cellular GSH depletion, resulting in increased ROS accumulation. This synergistic effect could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). The synergistic effect of SAS and VC was also noted in prostate cancer xenografts and correlated with immunohistochemistry results.

Conclusions

Our results strongly indicate that SAS, a relatively non-toxic drug that targets cystine transporters, in combination with VC may be superior to their single applications in the treatment of prostate cancer.

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Abbreviations

VC:

Vitamin C

ROS:

Reactive oxygen species

SAS:

Sulfasalazine

Xc− :

The xc− cystine/glutamate antiporter

NAC:

N-Acetyl-L-cysteine

SVCTs:

Sodium vitamin C co-transporters

LIP:

Labile iron pool

GLUTs:

Facilitative glucose transporters

DHA:

Dehydroascorbate

NADPH:

Nicotinamide adenine dinucleotide phosphate

CAM:

Complementary and alternative medicine

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Acknowledgments

We are grateful to all members of the Xiangsong Zhang group for contributions to this project. We thank QiaoSu, Gangyin Zhao and all members from the animal care facility at The First Affiliated Hospital of Sun Yat-sen University for animal management. We thank Yali Tang for technical supporting with FACS analysis.

This work is supported by the Science and Technology Planning Project of Guangdong Province grant 2017B020210001, the Science and Technology Program of Guangzhou grant 201607010353, the Training program of the Major Research Plan of Sun Yat-Sen University grant 17ykjc10 (to X.S.Z.), the Science and Technology Planning Project of Guangdong Province (Grant No. 2016B030307003), the Science and Technology Planning Project of Guangdong Province (Grant No. 2017B020210001) and the National Natural Science Foundation of China (Grant No.81501509).

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  1. Zhoulei Li and Xiangsong Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Zijie Zheng, Ganhua Luo, Xinchong Shi, Yali Long, Wanqing Shen, Zhoulei Li & Xiangsong Zhang

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  1. Zijie Zheng
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Correspondence to Zhoulei Li or Xiangsong Zhang.

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All experiments were approved by the Institutional Animal Care and Use Committee of The First Affiliated Hospital of Sun Yat-sen University and conformed to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

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Zheng, Z., Luo, G., Shi, X. et al. The Xc− inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism. Cell Oncol. 43, 95–106 (2020). https://doi.org/10.1007/s13402-019-00474-8

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