Department of Oncology, Panyu Central Hospital, Guangzhou, China.
Cancer Institute of Panyu, Guangzhou, China.
Curr Pharm Des. 2023;29(32):2591-2600. doi: 10.2174/0113816128263069231010111347.
Osimertinib (Osm) is the preferred treatment for non-small cell lung cancer (NSCLC) patients with the epidermal growth factor receptor (EGFR) T790M mutation. Nevertheless, the resistance of NSCLC cells to Osm will eventually develop, which remains the biggest obstacle to treating such diseases. Raddeanin A (RA) exhibits a potent anti-tumor effect on various types of cancer cells. In this study, we aimed to investigate whether RA suppresses NSCLC growth and increases the therapeutic effect of Osm.
The effects of RA on inhibiting NSCLC cell viability and proliferation were tested using cell counting kit 8 (CCK-8) and EdU assay. The roles of RA in improving the anti-tumor effect of Osm were tested with CCK-8 and colony formation assays. The roles of RA in regulating reactive oxygen species (ROS)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis were assessed using quantitative real- time PCR (qRT-PCR) and western blotting analysis.
RA treatment decreased A549 and H1975 cell viability in a dose- and time-dependent way. RA inhibited NSCLC cell proliferation and tumor growth . Mechanistically, RA induced ROS overgeneration and resulted in subsequent NLRP3-mediated pyroptosis. In particular, combination treatment with Osm and RA reduced cell viability and clonogenic growth capacity more efficiently than Osm mono treatment in A549 and H1975 cells. Combination treatment also promoted NLRP3-mediated pyroptosis more efficiently than Osm mono treatment.
RA inhibited the NSCLC growth and increased the anti-tumor role of Osm in NSCLC by facilitating ROS/NLRP3-mediated pyroptosis. These results suggested that combination therapy with RA and Osm might be an effective strategy to treat Osm-resistant NSCLC.
奥希替尼（Osimertinib，Osm）是表皮生长因子受体（Epidermal Growth Factor Receptor，EGFR）T790M 突变的非小细胞肺癌（Non-Small Cell Lung Cancer，NSCLC）患者的首选治疗药物。然而，NSCLC 细胞对 Osm 的耐药性最终会发展，这仍然是治疗此类疾病的最大障碍。竹节香附素 A（Raddeanin A，RA）对多种类型的癌细胞具有强大的抗肿瘤作用。在这项研究中，我们旨在研究 RA 是否能抑制 NSCLC 生长并增加 Osm 的治疗效果。
用细胞计数试剂盒 8（Cell Counting Kit 8，CCK-8）和 EdU 检测法检测 RA 抑制 NSCLC 细胞活力和增殖的作用。用 CCK-8 和集落形成实验检测 RA 提高 Osm 抗肿瘤作用的作用。用实时定量 PCR（Quantitative Real-Time PCR，qRT-PCR）和 Western blot 分析评估 RA 在调节活性氧（Reactive Oxygen Species，ROS）/核苷酸结合寡聚结构域样受体家族成员 3（Nucleotide-Binding Oligomerization Domain-Like Receptor Family Member 3，NLRP3）介导的细胞焦亡中的作用。
RA 处理以剂量和时间依赖的方式降低 A549 和 H1975 细胞活力。RA 抑制 NSCLC 细胞增殖和肿瘤生长。机制上，RA 诱导 ROS 过度生成，导致随后的 NLRP3 介导的细胞焦亡。特别是，与 Osm 单药治疗相比，Osm 和 RA 的联合治疗更有效地降低 A549 和 H1975 细胞的细胞活力和集落形成能力。联合治疗也比 Osm 单药治疗更有效地促进 NLRP3 介导的细胞焦亡。
RA 通过促进 ROS/NLRP3 介导的细胞焦亡来抑制 NSCLC 生长并增加 Osm 在 NSCLC 中的抗肿瘤作用。这些结果表明，RA 和 Osm 的联合治疗可能是治疗 Osm 耐药性 NSCLC 的有效策略。
