Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Jiangxi Cancer Hospital, Nanchang, China.
Cell Prolif. 2020 Mar;53(3):e12777. doi: 10.1111/cpr.12777. Epub 2020 Feb 5.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC.
We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC-QTOF/MS was used for untargeted metabolomic relative quantitation analysis.
We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways.
HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti-cancer effects.
信号转导子和转录激活子 3（STAT3）在许多癌症中持续激活和过度表达，包括非小细胞肺癌（NSCLC）。我们最近开发了 HJC0152 作为一种口服活性的 STAT3 抑制剂。本研究主要研究了 HJC0152 在 NSCLC 中的作用和作用机制。
我们通过 MTT 分析检测细胞增殖，通过划痕愈合和 Transwell 分析检测细胞迁移，通过 Western blot 检测蛋白水平，通过流式细胞术检测细胞凋亡和活性氧（ROS）水平。建立裸鼠肿瘤发生模型进行体内实验。采用 UHPLC-QTOF/MS 进行非靶向代谢组相对定量分析。
我们发现 HJC0152 通过调节 STAT3 信号通路和代谢，在体外对人 NSCLC 细胞和 NSCLC 异种移植瘤具有活性，在体内对 NSCLC 细胞和 NSCLC 异种移植瘤具有活性。HJC0152 有效地降低了 NSCLC 细胞的增殖，促进了 ROS 的产生，诱导了 A549 和 H460 NSCLC 细胞的凋亡，引发了 DNA 损伤，并降低了其迁移能力。此外，HJC0152 显著抑制了 A549 异种移植瘤在体内的生长。HJC0152 还影响了代谢，显著降低和扰乱了嘌呤、谷胱甘肽和嘧啶代谢途径中几种代谢物的水平。
HJC0152 降低了细胞清除自由基的能力，导致 ROS 的产生和积累以及细胞凋亡。本研究为进一步将 HJC0152 开发为 NSCLC 的潜在治疗方法提供了依据，并深入了解了 HJC0152 发挥抗癌作用的机制。
