目的： 探讨雷替曲塞对顺铂耐受的结直肠癌细胞（R-HCT116）化疗敏感性的影响，并初步探究其分子机制。方法： 建立顺铂耐受的结直肠癌细胞株R-HCT116，CCK-8法检测结直肠癌细胞（HCT116）和R-HCT116细胞活力的影响；Annexin V-FITC/PI细胞凋亡检测试剂盒检测各组R-HCT116细胞凋亡情况；通过透射电子显微镜观察各处理组R-HCT116细胞自噬体；免疫荧光染色检测各处理组R-HCT116细胞中LC3表达；蛋白免疫印迹法检测分析自噬蛋白及PI3K/Akt/mTOR通路相关蛋白表达情况。结果： 不同浓度的雷替曲塞（0.1、0.5、1.0、2.0 μg·ml^-1）处理HCT116细胞48 h和72 h，细胞存活率下降且呈剂量依赖性（P<0.05）；与顺铂组比较，使用0.5、1.0、2.0 μg·ml^-1的雷替曲塞联合20 μg·ml^-1顺铂作用的R-HCT116细胞存活率下降，细胞凋亡率上升，细胞中自噬体数量增加，LC3表达荧光强度增加，Beclin-1、LC3-Ⅱ/LC3-I表达增高而P62蛋白表达降低；细胞中p-PI3K/PI3K、p-Akt/Akt和p-mTOR/mTOR均降低（均P<0.05）。结论： 雷替曲塞能明显增强结直肠癌细胞HCT116细胞对顺铂化疗敏感性，其机制可能与增强细胞自噬有关。

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