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Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc − cystine transporter: a new action for an old drug

Leukemia volume 15, pages 1633–1640 (2001)Cite this article

Abstract

Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their micro-environment. Accordingly, we previously suggested that the xc − plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on xc − inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the xc − transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of xc −-mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90–100% tumor growth suppression, relative to controls, was obtained. The xc − cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine.

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Acknowledgements

Dr CT Beer and Dr MC Robertson (BC Cancer Agency, Canada) are thanked for helpful discussions, and DJ Buckley (Cincinnati Medical Center, USA) for preparing the northern blots. Dr S Bannai (University of Tsukuba, Ibaraki, Japan) is thanked for providing the 4F2hc and xCT cDNA probes, and the Department of Advanced Therapeutics of the BC Cancer Agency for supplying DoHH2 cells. This study was supported by the BC Cancer Foundation, with core support from the BC Cancer Agency (PWG), and in part by NIH grant No. DK53452 and the Ohio Cancer Research Associates (ARB).

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  1. Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada

    PW Gout, CR Simms & N Bruchovsky

  2. College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH, USA

    AR Buckley

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Gout, P., Buckley, A., Simms, C. et al. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc − cystine transporter: a new action for an old drug. Leukemia 15, 1633–1640 (2001). https://doi.org/10.1038/sj.leu.2402238

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