Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518036, China; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen, Guangdong 518036, China.
Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China.
Phytomedicine. 2022 Oct;105:154364. doi: 10.1016/j.phymed.2022.154364. Epub 2022 Jul 28.
Developing novel and effective drugs with less toxicity is urgent for non-small cell lung cancer (NSCLC) therapy. Xanthotoxol (Xan) is the major natural component of the medical plant Angelica dahurica with potential anti-cancer activities.
In this study, we aimed to demonstrate the effect and underlying mechanism of Xan in NSCLC and evaluate the effectiveness of Xan in NSCLC patients.
CCK8, colony formation, EdU, flow cytometry, and transwell assays were carried out to investigate the anti-NSCLC activity of Xan in vitro. In addition, the xenograft mouse model was established to evaluate the anti-NSCLC effect of Xan in vivo. Moreover, bioinformatics analysis was performed to establish a prediction model based on RNA sequencing data. Furthermore, Western blot was used to detect the expression of proteins regulated by Xan.
Xan inhibited the cell viability, colony formation capacity, DNA replication, cell cycle transition, migration and invasion, as well as inducing apoptosis of NSCLC cells. In addition, Xan suppressed NSCLC xenograft growth in vivo without obvious toxicity. Interestingly, bioinformatics analyses based on the RNA sequencing data indicated that Xan exerted inhibitory effects on NSCLC cells by down-regulating signals contributing to NSCLC progression and demonstrated that Xan was effective in ameliorating the prognosis of NSCLC patients with a new proposed prediction model. Moreover, Xan was shown to regulate cell cycle arrest, apoptosis, and epithelial-mesenchymal transition (EMT)-associated genes through downregulating PI3K-AKT signaling, thus suppressing NSCLC proliferation and metastasis.
Taken together, our work proved that Xan induced cell cycle arrest, facilitated apoptosis, and inhibited EMT processes through downregulating the PI3K-AKT pathway to suppress NSCLC progress. Moreover, we also proposed a new model for evaluating Xan as a novel and effective drug in NSCLC treatments.
开发毒性更小的新型有效药物是治疗非小细胞肺癌（NSCLC）的当务之急。花椒毒素（Xan）是药用植物白芷的主要天然成分，具有潜在的抗癌活性。
本研究旨在证明 Xan 在 NSCLC 中的作用及作用机制，并评估 Xan 在 NSCLC 患者中的疗效。
采用 CCK8、集落形成、EdU、流式细胞术和 Transwell 检测体外 Xan 对 NSCLC 的抑制作用。此外，建立异种移植小鼠模型，评价 Xan 在体内对 NSCLC 的抑制作用。此外，进行生物信息学分析，基于 RNA 测序数据建立预测模型。进一步采用 Western blot 检测 Xan 调控的蛋白表达。
Xan 抑制 NSCLC 细胞活力、集落形成能力、DNA 复制、细胞周期转换、迁移和侵袭，并诱导细胞凋亡。此外，Xan 在体内抑制 NSCLC 异种移植瘤生长而无明显毒性。有趣的是，基于 RNA 测序数据的生物信息学分析表明，Xan 通过下调促进 NSCLC 进展的信号，对 NSCLC 细胞发挥抑制作用，并提出了一个新的预测模型，表明 Xan 可改善 NSCLC 患者的预后。此外，Xan 通过下调 PI3K-AKT 信号通路，调节细胞周期阻滞、凋亡和上皮-间质转化（EMT）相关基因，从而抑制 NSCLC 的增殖和转移。
综上所述，我们的工作证明 Xan 通过下调 PI3K-AKT 通路诱导细胞周期阻滞、促进凋亡、抑制 EMT 过程，从而抑制 NSCLC 的进展。此外，我们还提出了一个新的模型，用于评估 Xan 作为 NSCLC 治疗的新型有效药物。
