The xc− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine
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- Guan, J., Lo, M., Dockery, P. et al. Cancer Chemother Pharmacol (2009) 64: 463. doi:10.1007/s00280-008-0894-4
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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.