Cancer Chemotherapy and Pharmacology

, 64:463

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

Authors

  • Jun Guan
    • Department of Cancer EndocrinologyBC Cancer Agency, Research Centre
  • Maisie Lo
    • Department of Cancer GeneticsBC Cancer Agency, Research Centre
  • Peter Dockery
    • Department of AnatomyNational University of Ireland
  • Sarah Mahon
    • Department of SurgeryNational University of Ireland
  • Cristina M. Karp
    • Center for Advanced Biotechnology and MedicineRutgers University
  • Arthur R. Buckley
    • James L. Winkle College of PharmacyUniversity of Cincinnati Academic Health Center
  • Stephen Lam
    • Department of Cancer ImagingBC Cancer Agency, Research Centre
    • Department of Cancer EndocrinologyBC Cancer Agency, Research Centre
    • Department of Cancer EndocrinologyBC Cancer Agency, Research Centre
    • The Prostate Centre at Vancouver General Hospital and Department of Urologic SciencesUniversity of BC
Original Article

DOI: 10.1007/s00280-008-0894-4

Cite this article as:
Guan, J., Lo, M., Dockery, P. et al. Cancer Chemother Pharmacol (2009) 64: 463. doi:10.1007/s00280-008-0894-4

Abstract

Purpose

To determine whether the xc 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, xc expression, glutathione levels and response to highly specific xc 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 xc-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 xc 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.

Keywords

xc transporterCystineGlutathioneSmall-cell lung cancerSCLC xenograft modelSulfasalazine

Copyright information

© Springer-Verlag 2008