一种海洋来源ETP类化合物GQQ-ZML-2抑制H358细胞增殖作用与机制的研究

摘要：目的 探究化合物GQQ-ZML-2对H358细胞(KRASG12C)的增殖抑制作用并初步研究其作用机制。方法 采用磺酰罗丹明B法（SRB法）测定GQQ-ZML-2对不同KRAS突变的肿瘤细胞的细胞毒；采用流式细胞术检测细胞周期和细胞凋亡；利用荧光探针DCFH-DA检测细胞内总活性氧（ROS）水平；Western Blotting检测相关信号蛋白的表达水平；结果 GQQ-ZML-2选择性抑制H358细胞增殖，以浓度依赖的方式抑制克隆形成并将细胞周期阻滞于G2/M期而诱导细胞凋亡。机制研究表明GQQ-ZML-2引起KRAS G12C依赖的ROS产生，抑制AKT/mTOR和JAK2/STAT3信号通路。结论 GQQ-ZML-2是一种新型的具有选择性抑制H358细胞增殖作用的海洋来源化合物，其作用机制可能与诱导KRASG12C依赖的ROS增加相关。本文研究为开发新型的拮抗具有KRASG12C突变肿瘤的药物提供了实验依据。

Studies on the inhibitory effect and mechanism of ETPs compound GQQ-ZML-2 from marine products on the proliferation of H358 cells

Abstract: Objective To investigate the proliferation inhibitory effect of compound GQQ-ZML-2 on the of H358 cells (KRASG12C) and its mechanism. Methods The cytotoxicity of GQQ-ZML-2 to different cancer cells was determined by SRB method (SRB method). The cell cycle and apoptosis were detected by flow cytometry. Intracellular total reactive oxygen species (ROS) were detected by fluorescence probe DCFH-DA. The expression levels of related signaling proteins were detected by Western Blotting. Results GQQ-ZML-2 selectively inhibited the proliferation of H358 cells, inhibited clonal formation in a concentration-dependent manner, and induced cell apoptosis by blocking the cell cycle in G2/M phase. Mechanism studies have shown that GQQ-ZML-2 induces KRASG12C-dependent ROS production and inhibits AKT/mTOR and JAK2/STAT3 signaling pathways. Conclusion GQQ-ZML-2 is a novel marine compound that selectively inhibits the proliferation of H358 cells, and its mechanism relates to the induction of ROS increase dependent on KRASG12C. This study provides experimental basis to develop novel antagonistic agent for cancer with KRASG12Cmutant.