Doxsee Daniel W, Gout Peter W, Kurita Takeshi, Lo Maisie, Buckley Arthur R, Wang Yuwei, Xue Hui, Karp Cristina M, Cutz Jean-Claude, Cunha Gerald R, Wang Yu-Zhuo
Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, Canada.
Prostate. 2007 Feb 1;67(2):162-71. doi: 10.1002/pros.20508.
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.
Cultures were evaluated for growth dependence on exogenous cystine, x(c)(-) transporter expression, response to SASP (growth and glutathione content). In vivo, effect of SASP was determined on subrenal capsule xenograft growth.
Cystine omission from culture medium arrested DU-145 and PC-3 cell proliferation; both cell lines expressed the x(c)(-) transporter and were growth inhibited by SASP (IC(50)s: 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.
SASP-induced cystine/cysteine starvation leading to glutathione depletion may be useful for therapy of prostate cancers dependent on extracellular cystine.
某些癌症的生长依赖于从周围环境摄取胱氨酸/半胱氨酸。在此，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以及对柳氮磺胺吡啶（SASP）的敏感性，SASP是x(c)(-)胱氨酸转运体的强效抑制剂。
评估细胞培养物对外源胱氨酸的生长依赖性、x(c)(-)转运体表达、对SASP的反应（生长和谷胱甘肽含量）。在体内，测定SASP对肾包膜下异种移植瘤生长的影响。
从培养基中去除胱氨酸会使DU - 145和PC - 3细胞增殖停滞；这两种细胞系均表达x(c)(-)转运体，并受到SASP的生长抑制（IC50分别为0.20和0.28 mM）。SASP诱导的生长抑制与细胞内谷胱甘肽含量大幅降低有关——这两种效应均基于胱氨酸饥饿。腹腔注射SASP显著抑制DU - 145和PC - 3异种移植瘤的生长，且对宿主无明显毒性。
SASP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治疗有用。
