Sulfasalazine (SSZ) is widely known as an xCT inhibitor suppressing CD44v9-expressed cancer stem-like cells (CSCs) being related to redox regulation. Cholangiocarcinoma (CCA) has a high recurrence rate and no effective chemotherapy. A recent report revealed high levels of CD44v9-positive cells in CCA patients. Therefore, a combination of drugs could prove a suitable strategy for CCA treatment via individual metabolic profiling. We examined the effect of xCT-targeted CD44v9-CSCs using sulfasalazine combined with cisplatin (CIS) or gemcitabine in CCA in vitro and in vivo models and did NMR-based metabolomics analysis of xenograft mice tumor tissues. Our findings suggest that combined SSZ and CIS leads to a higher inhibition of cell proliferation and induction of cell death than CIS alone in both in vitro and in vivo models. Xenograft mice showed that the CD44v9-CSC marker and CK-19-CCA proliferative marker were reduced in the combination treatment. Interestingly, different metabolic signatures and significant metabolites were observed in the drug-treated group compared with the control group that revealed the cancer suppression mechanisms. SSZ could improve CCA therapy by sensitization to CIS through killing CD44v9-positive cells and modifying the metabolic pathways, in particular tryptophan degradation (i.e., kynurenine pathway, serotonin pathway) and nucleic acid metabolism.

中文翻译：

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柳氮磺吡啶在体外和体内模型中均能改变代谢谱并增强对胆管癌细胞的顺铂化学敏感性

柳氮磺吡啶（SSZ）作为抑制CT44v9表达的癌症干样细胞（CSC）的xCT抑制剂而广为人知，该干细胞与氧化还原调节相关。胆管癌（CCA）的复发率很高，并且没有有效的化学疗法。最近的一份报告显示，CCA患者中CD44v9阳性细胞水平高。因此，药物组合可以证明通过个体代谢谱分析进行CCA治疗的合适策略。我们在体外和体内模型中研究了柳氮磺吡啶与顺铂（CIS）或吉西他滨联用xCT靶向CD44v9-CSC的效果，并在异种移植小鼠肿瘤组织中进行了基于NMR的代谢组学分析。我们的发现表明，在体外和体内模型中，与单独使用CIS相比，SSZ和CIS组合对细胞增殖的抑制作用更高，并且对细胞死亡的诱导程度更高。异种移植小鼠显示，在联合治疗中，CD44v9-CSC标志物和CK-19-CCA增殖标志物减少。有趣的是，与显示出癌症抑制机制的对照组相比，在药物治疗组中观察到了不同的代谢特征和重要的代谢产物。SSZ可以通过杀死CD44v9阳性细胞并修饰代谢途径，特别是色氨酸降解（即犬尿氨酸途径，5-羟色胺途径）和核酸代谢，通过对CIS敏感来改善CCA治疗。