HJC0152通过抑制STAT3和调节新陈代谢来抑制人类非小细胞肺癌。,Cell Proliferation

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HJC0152通过抑制STAT3和调节新陈代谢来抑制人类非小细胞肺癌。
Cell Proliferation ( IF 5.9 ) Pub Date : 2020-02-05 , DOI: 10.1111/cpr.12777
Lu Lu ₁ , Hang Li ₁ , Xin Wu ₁ , Jun Rao ₂ , Jia Zhou ₃ , Saijun Fan ₁ , Qiang Shen ₄

Affiliation

目标信号转导和转录激活因子3（STAT3）在包括非小细胞肺癌（NSCLC）在内的许多癌症中被组成性激活和过表达。我们最近开发了HJC0152作为口服活性STAT3抑制剂。这项研究的重点是调查HJC0152在非小细胞肺癌中的作用和作用机制。材料和方法我们通过MTT分析法分析了细胞增殖，通过伤口愈合和transwell分析法分析了细胞迁移，通过Western印迹分析了蛋白质水平，并通过流式细胞术分析了细胞凋亡和活性氧（ROS）水平。建立裸鼠肿瘤发生模型用于体内实验。UHPLC-QTOF / MS用于非目标代谢组学相对定量分析。结果我们发现，HJC0152通过调节STAT3信号传导和代谢，在体外对人NSCLC细胞和体内NSCLC异种移植肿瘤表现出活性。HJC0152有效降低了A549和H460 NSCLC细胞的NSCLC细胞增殖，促进了ROS的产生，诱导了细胞凋亡，触发了DNA损伤并降低了运动性。此外，HJC0152在体内显着抑制了A549异种移植肿瘤的生长。HJC0152还影响代谢，显着降低和扰动嘌呤，谷胱甘肽和嘧啶代谢途径中几种代谢物的水平。结论HJC0152降低了细胞清除自由基的能力，导致ROS的产生，积累和凋亡。

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HJC0152 suppresses human non-small-cell lung cancer by inhibiting STAT3 and modulating metabolism.

OBJECTIVES 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

更新日期：2020-02-05

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