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

  • Jun Guan
  • Maisie Lo
  • Peter Dockery
  • Sarah Mahon
  • Cristina M. Karp
  • Arthur R. Buckley
  • Stephen Lam
  • Peter W. Gout
  • Yu-Zhuo Wang
Original Article

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 transporter Cystine Glutathione Small-cell lung cancer SCLC xenograft model Sulfasalazine 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jun Guan
    • 1
  • Maisie Lo
    • 2
  • Peter Dockery
    • 3
  • Sarah Mahon
    • 4
  • Cristina M. Karp
    • 5
  • Arthur R. Buckley
    • 6
  • Stephen Lam
    • 7
  • Peter W. Gout
    • 1
  • Yu-Zhuo Wang
    • 1
    • 8
  1. 1.Department of Cancer EndocrinologyBC Cancer Agency, Research CentreVancouverCanada
  2. 2.Department of Cancer GeneticsBC Cancer Agency, Research CentreVancouverCanada
  3. 3.Department of AnatomyNational University of IrelandGalwayIreland
  4. 4.Department of SurgeryNational University of IrelandGalwayIreland
  5. 5.Center for Advanced Biotechnology and MedicineRutgers UniversityPiscatawayUSA
  6. 6.James L. Winkle College of PharmacyUniversity of Cincinnati Academic Health CenterCincinnatiUSA
  7. 7.Department of Cancer ImagingBC Cancer Agency, Research CentreVancouverCanada
  8. 8.The Prostate Centre at Vancouver General Hospital and Department of Urologic SciencesUniversity of BCVancouverCanada

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