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Guan, J,Lo, M,Dockery, P,Mahon, S,Karp, CM,Buckley, AR,Lam, S,Gout, PW,Wang, YZ
2009
July
Cancer Chemotherapy And Pharmacology
The x (c) (-) cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine
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x(c)(-) transporter Cystine Glutathione Small-cell lung cancer SCLC xenograft model Sulfasalazine GROWTH-INHIBITORY ACTIVITY CYSTINE UPTAKE IN-VITRO TUMOR PROGRESSION DRUG-RESISTANCE LYMPHOMA GROWTH MODELS ACID PROLIFERATION TRANSPORTER
64
463
472
To determine whether the x (c) (-) 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, 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.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 IC(50)s 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 mu M) indicating they were primarily due to cystine starvation. Without major side-effects, SASP (i.p.) restrained growth of NCI-H69 cell xenografts (similar to 50%) and, importantly, substantially inhibited growth of the clinically more relevant LU6-SCLC tissue xenografts (similar to 70% by stereological analysis), reducing tumor glutathione contents.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.
DOI 10.1007/s00280-008-0894-4
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