Zheng Wubin, Ge Zhifa, Wu Qingwei, Wan Haoyue, Sun Junjie, Nai Yongjun, Lv Chengyu
Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, 68 Changle Rd., Nanjing, 210006, Jiangsu, China.
Dig Dis Sci. 2025 Apr 16. doi: 10.1007/s10620-025-09021-y.
PARP inhibitors, effective in BRCA-mutated cancers, show potential in gastric cancer (GC) where homologous recombination defects (e.g., BRCA1/2 mutations) are common. Olaparib, a PARP inhibitor, upregulates PD-L1, suggesting synergy with PD-1 inhibitors for enhanced GC therapy.
Using CCK-8 screening of 867 drugs, olaparib demonstrated potent GC cell inhibition. Western blot and qRT-PCR assessed PD-L1, c-MYC, COX-2, and NF-κB pathway proteins (p65/p-p65). Functional assays (Transwell, wound healing, colony formation) evaluated olaparib's effects on GC cell proliferation, migration, and invasion. A GC mouse model tested olaparib combined with anti-PD1. TCGA and Kaplan-Meier analyzed PARP expression-prognosis correlations.
Olaparib suppressed GC cell proliferation, migration, and invasion in vitro. Western blot revealed upregulated c-MYC, COX-2, p65, p-p65, and PD-L1, confirmed by qRT-PCR for PD-L1. Low PARP expression correlated with better GC patient survival. In vivo, olaparib synergized with anti-PD1 to enhance tumor suppression.
Olaparib activates the NF-κB/c-MYC pathway to elevate PD-L1, supporting its combination with PD-1 inhibitors as a promising GC therapeutic strategy.
聚（ADP-核糖）聚合酶（PARP）抑制剂对BRCA突变的癌症有效，在同源重组缺陷（如BRCA1/2突变）常见的胃癌（GC）中显示出潜力。奥拉帕利是一种PARP抑制剂，可上调程序性死亡受体配体1（PD-L1），提示其与PD-1抑制剂联合使用可增强GC治疗效果。
通过细胞计数试剂盒-8（CCK-8）对867种药物进行筛选，结果显示奥拉帕利对GC细胞具有强效抑制作用。蛋白质免疫印迹法（Western blot）和实时定量逆转录聚合酶链反应（qRT-PCR）检测PD-L1、c-MYC、环氧化酶-2（COX-2）和核因子κB（NF-κB）信号通路蛋白（p65/p-p65）。功能试验（Transwell小室实验、伤口愈合实验、集落形成实验）评估奥拉帕利对GC细胞增殖、迁移和侵袭的影响。利用GC小鼠模型检测奥拉帕利与抗PD-1抗体联合使用的效果。癌症基因组图谱（TCGA）数据库和Kaplan-Meier分析评估PARP表达与预后的相关性。
奥拉帕利在体外可抑制GC细胞的增殖、迁移和侵袭。Western blot结果显示c-MYC、COX-2、p65、p-p65和PD-L1表达上调，qRT-PCR检测结果证实了PD-L1的上调。PARP低表达与GC患者更好的生存率相关。在体内，奥拉帕利与抗PD-1抗体联合使用可增强肿瘤抑制作用。
奥拉帕利激活NF-κB/c-MYC信号通路以提高PD-L1表达，支持其与PD-1抑制剂联合使用作为一种有前景的GC治疗策略。
