Dai Zunyan, Huang Ying, Sadee Wolfgang, Blower Paul
Program of Pharmacogenomics, Department of Pharmacology and the Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus Ohio 43210, USA.
J Med Chem. 2007 Apr 19;50(8):1896-906. doi: 10.1021/jm060960h. Epub 2007 Mar 17.
Glutathione detoxification has been broadly implicated in resistance to chemotherapy. This study explores the relationship between chemical structure and GSH-mediated chemoresistance. System xc-, the heterodimeric cystine/glutamate exchanger composed of SLC7A11 and SLC3A2, plays a role in maintaining cellular glutathione (GSH) levels. Previous results show that SLC7A11 expression negatively correlates with drug potency across the National Cancer Institute's 60 cell lines for compounds susceptible to GSH-mediated chemoresistance. The number of significant SLC7A11-drug correlations was much greater than those of other genes tested, suggesting that SLC7A11 plays a critical role. Approximately 15% of a curated set of 3045 compounds yielded significant negative SLC7A11 correlations. These compounds tend to contain structural features amenable to GSH reactivity, such as Mannich bases. In cell lines strongly expressing SLC7A11, the potency of selected compounds, was enhanced by inhibition of SLC7A11. This system provides a rapid screen for detecting susceptibility of anticancer drugs to GSH-mediated resistance.
谷胱甘肽解毒作用在化疗耐药性中具有广泛影响。本研究探讨了化学结构与谷胱甘肽介导的化疗耐药性之间的关系。系统xc-是由SLC7A11和SLC3A2组成的异二聚体胱氨酸/谷氨酸交换体，在维持细胞内谷胱甘肽（GSH）水平中发挥作用。先前的结果表明，对于易受谷胱甘肽介导的化疗耐药性影响的化合物，在国立癌症研究所的60种细胞系中，SLC7A11的表达与药物效力呈负相关。与其他测试基因相比，显著的SLC7A11-药物相关性数量要多得多，这表明SLC7A11起着关键作用。在精心挑选的3045种化合物中，约15%与SLC7A11呈显著负相关。这些化合物往往含有易于与谷胱甘肽发生反应的结构特征，如曼尼希碱。在强烈表达SLC7A11的细胞系中，通过抑制SLC7A11可增强所选化合物的效力。该系统为检测抗癌药物对谷胱甘肽介导的耐药性的敏感性提供了一种快速筛选方法。
