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The x −c cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine

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Abstract

Purpose

To determine whether the x −c cystine transporter could be a useful therapeutic target for small-cell lung cancer (SCLC).

Methods

Human SCLC cell cultures were examined for growth dependence on extracellular cystine, x −c expression, glutathione levels and response to highly specific x −c inhibitors, i.e., monosodium glutamate (MSG) and the anti-inflammatory drug, sulfasalazine (SASP). In studying tumor growth inhibition by SASP, use was also made of a novel SCLC tissue xenograft model, LU6-SCLC, derived from a chemoresistant patient’s SCLC specimen.

Results

Growth of NCI-H69 and NCI-H82 SCLC cells greatly depended on x −c -mediated uptake of cystine. SASP substantially reduced their glutathione levels (>70%; 0.3 mM SASP; 24 h) and growth (72 h) with IC50s of 0.21 and 0.13 mM, respectively; MSG also inhibited growth markedly. Both SASP- and MSG-induced growth arrests were largely prevented by cystine uptake-enhancing 2-mercaptoethanol (66 μM) indicating they were primarily due to cystine starvation. Without major side-effects, SASP (i.p.) restrained growth of NCI-H69 cell xenografts (~50%) and, importantly, substantially inhibited growth of the clinically more relevant LU6-SCLC tissue xenografts (~70% by stereological analysis), reducing tumor glutathione contents.

Conclusions

The x −c cystine/glutamate antiporter is potentially useful as a target for therapy of SCLC based on glutathione depletion. Sulfasalazine may be readily used for this approach, especially in combination chemotherapy.

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Acknowledgments

The authors thank Dan Doxsee, Hui Xue, Margaret Sutcliffe and Lily Wei for technical assistance. This study was financially supported by grants from the National Cancer Institute of Canada and British Columbia Lung Association (Y.Z.W), Canadian Institutes of Health Research (P.W.G/Y.Z), BC Cancer Foundation (P.W.G), Genome Canada (S.L) and National Breast Cancer Institute of Ireland (S.M). ML was supported by Sr. Graduate Studentship Awards from the Natural Sciences and Engineering Research Council of Canada, Canadian Institutes of Health Research and Michael Smith Foundation for Health Research

Conflict of interest statement

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Authors and Affiliations

  1. Department of Cancer Endocrinology, BC Cancer Agency, Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

    Jun Guan, Peter W. Gout & Yu-Zhuo Wang

  2. Department of Cancer Genetics, BC Cancer Agency, Research Centre, Vancouver, BC, V5Z 1L3, Canada

    Maisie Lo

  3. Department of Anatomy, National University of Ireland, Galway, Ireland

    Peter Dockery

  4. Department of Surgery, National University of Ireland, Galway, Ireland

    Sarah Mahon

  5. Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, 08854, USA

    Cristina M. Karp

  6. James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, OH, 45267-0004, USA

    Arthur R. Buckley

  7. Department of Cancer Imaging, BC Cancer Agency, Research Centre, Vancouver, BC, V5Z 1L3, Canada

    Stephen Lam

  8. The Prostate Centre at Vancouver General Hospital and Department of Urologic Sciences, University of BC, Vancouver, BC, V6T 2B5, Canada

    Yu-Zhuo Wang

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  1. Jun Guan
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  2. Maisie Lo
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Correspondence to Peter W. Gout or Yu-Zhuo Wang.

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Guan, J., Lo, M., Dockery, P. et al. The x −c cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine. Cancer Chemother Pharmacol 64, 463–472 (2009). https://doi.org/10.1007/s00280-008-0894-4

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  • DOI: https://doi.org/10.1007/s00280-008-0894-4

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