The x c − cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine
| Autor: | Peter W. Gout, Yuzhuo Wang, Sarah Mahon, Peter Dockery, Arthur R. Buckley, Jun Guan, Maisie Lo, Stephen Lam, Cristina M. Karp |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research Lung Neoplasms Amino Acid Transport System y+ Antiporter medicine.medical_treatment Cystine Mice SCID Toxicology Targeted therapy Inhibitory Concentration 50 Mice chemistry.chemical_compound Drug Delivery Systems Mice Inbred NOD Sulfasalazine Cell Line Tumor Sodium Glutamate medicine Animals Humans Pharmacology (medical) Carcinoma Small Cell Lung cancer neoplasms Pharmacology business.industry Anti-Inflammatory Agents Non-Steroidal Glutamate receptor Cancer Biological Transport Glutathione respiratory system medicine.disease Xenograft Model Antitumor Assays humanities respiratory tract diseases Gene Expression Regulation Neoplastic Oncology chemistry Immunology Cancer research business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 64:463-472 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | 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 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 approximately microM) indicating they were primarily due to cystine starvation. Without major side-effects, SASP (i.p.) restrained growth of NCI-H69 cell xenografts (approximately 50%) and, importantly, substantially inhibited growth of the clinically more relevant LU6-SCLC tissue xenografts (approximately 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. |
| Databáze: | OpenAIRE |
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