Sulfasalazine-induced cystine starvation: Potential use for prostate cancer therapy
Sulfasalazine-induced cystine starvation: Potential use for prostate cancer therapy
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DOI：
10.1002/pros.20508
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发表时间：
2007-02-01
期刊：
影响因子：
2.8
通讯作者：
Wang, Yu-Zhuo
中科院分区：
文献类型：
--
作者：
Doxsee, Daniel W.;Gout, Peter W.;Wang, Yu-Zhuo
背景。某些癌症的生长依赖于从环境中摄取胱氨酸/半胱氨酸。在这里，我们检测了晚期人类前列腺癌细胞系DU-145和PC-3对细胞外胱氨酸的依赖性和对磺胺吡啶（SASP）的敏感性，SASP是x(c)（-）胱氨酸转运体的有效抑制剂。培养物的生长对外源胱氨酸的依赖性、X.转运蛋白的表达、对SASP（生长和谷胱甘肽含量）的响应进行了评估。在体内，测定了SASP对肾下包膜异种移植物生长的影响。培养基中胱氨酸缺失阻碍了DU-145和PC-3细胞的增殖；两种细胞系均表达xc-转运体，SASP对其生长均有抑制作用（TC50S分别为0.20和0.28 mM）。ssp诱导的生长抑制与细胞谷胱甘肽含量的大量减少有关——这两种效应都是基于胱氨酸饥饿。SASP （i.p）显著抑制DU-145和PC-3异种移植物的生长，对宿主无明显毒性。ssp诱导的胱氨酸/半胱氨酸饥饿导致谷胱甘肽耗竭可能对依赖细胞外胱氨酸的前列腺癌的治疗有用。(c) 2006Wiley-Liss, Inc。
BACKGROUND. Certain cancers depend for growth on uptake of cystine/cysteine from their environment. Here we examined advanced human prostate cancer cell lines, DU-145 and PC-3, for dependence on extracellular cystine and sensitivity to sulfasalazine (SASP), a potent inhibitor of the x(c)(-) cystine transporter.METHODS. Cultures were evaluated for growth dependence on exogenous cystine, X. transporter expression, response to SASP (growth and glutathione content). In vivo, effect of SASP was determined on subrenal capsule xenograft growth.RESULTS. Cystine omission from culture medium arrested DU-145 and PC-3 cell proliferation; both cell lines expressed the xc- transporter and were growth inhibited by SASP (TC50S: 0.20 and 0.28 mM, respectively). SASP-induced growth inhibition was associated with vast reductions in cellular glutathione content-both effects based on cystine starvation. SASP (i.p.) markedly inhibited growth of DU-145 and PC-3 xenografts without major toxicity to hosts.CONCLUSIONS. SASP-induced cystine/cysteine starvation leading to glutathione depletion may be useful for therapy of prostate cancers dependent on extracellular cystine. (c) 2006Wiley-Liss, Inc.