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Abstract：
Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.
摘要：
胆管癌（CCA）是一种由于诊断困难和治疗选择有限而预后不良的癌症。强调迫切需要新的靶向治疗。在临床环境中，我们发现胆汁中的白三烯水平高于血清。手术切除样品的免疫组织化学分析还显示，CysLT受体1（CysLTR1）在CCA中的表达高于正常胆管组织，促使我们研究白三烯作为CCA的潜在治疗靶点。使用表达CysLTR1的CCA细胞系的体外研究表明，CysLTR1的主要配体白三烯D4促进细胞增殖，AKT和细胞外信号调节激酶1/2（ERK1/2）的磷酸化增加。此外,用两种临床上可用的抗过敏药物齐留通治疗，CysLT形成的抑制剂，和孟鲁司特,一种CysLTR1抑制剂对细胞增殖和迁移能力有抑制作用，伴随着AKT和ERK1/2的磷酸化降低。此外，两种药物的同时给药协同增强了对细胞增殖的抑制作用。我们的研究表明，使用这些药物可能代表了一种通过药物重新定位治疗CCA的新方法。
