The xc− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine
- First Online:
To determine whether the xc− cystine transporter could be a useful therapeutic target for small-cell lung cancer (SCLC).
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.
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.
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.
Keywordsxc− transporter Cystine Glutathione Small-cell lung cancer SCLC xenograft model Sulfasalazine
- 18.Wang Y, Xue H, Cutz JC, Bayani J, Mawji NR, Chen WG, Goetz LJ, Hayward SW, Sadar MD, Gilks CB, Gout PW, Squire JA, Cunha GR, Wang YZ (2005) An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Lab Invest 85:1392–1404PubMedCrossRefGoogle Scholar
- 19.Cutz JC, Guan J, Bayani J, Yoshimoto M, Xue H, Sutcliffe M, English J, Flint J, LeRiche J, Yee J, Squire JA, Gout PW, Lam S, Wang YZ (2006) Establishment in severe combined immunodeficiency mice of subrenal capsule xenografts and transplantable tumor lines from a variety of primary human lung cancers: potential models for studying tumor progression-related changes. Clin Cancer Res 12:4043–4054PubMedCrossRefGoogle Scholar
- 21.Howard CV, Reed MG (2005) Unbiased stereology. Bios Scientific Publishers, Oxford, pp 256–277Google Scholar