胆管癌（CCA）通常诊断较晚，导致肿瘤切除不完全、产生耐药性和化疗疗效降低。姜黄素通过各种治疗特性具有抗癌活性的潜力，并且可以提高化疗的疗效。我们的目的是研究姜黄素和吉西他滨组合针对 CCA 的协同作用，针对 LAT2/谷氨酰胺途径。这种组合可协同抑制吉西他滨耐药 CCA 细胞 (KKU-213BGemR) 的增殖。它还导致 CCA 细胞凋亡和细胞周期停滞，其特征是高比例的细胞处于 S 期和 G2/M 期。 SLC7A8 的敲低会降低谷氨酰胺酶和谷氨酰胺合成酶的表达，从而抑制细胞增殖并使 CCA 细胞对吉西他滨治疗敏感。此外，体内实验表明，姜黄素和吉西他滨的组合可显着降低吉西他滨耐药的 CCA 异种移植小鼠模型中的肿瘤大小、肿瘤生长速度和 LAT2 表达。原位CCA仓鼠模型中肿瘤进展的抑制为临床应用提供了强有力的支持。总之，姜黄素通过诱导细胞凋亡，部分通过抑制 LAT2/谷氨酰胺途径，协同增强吉西他滨对吉西他滨耐药 CCA 的疗效。这种方法可能是治疗 CCA 患者对吉西他滨耐药的替代策略。© 2024。作者。

Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.© 2024. The Author(s).