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一种新型雷公藤红素类似物下调 NF-κB 并诱导人胰腺癌细胞线粒体凋亡途径。

A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer.

机构信息

Department of Surgery, The University of Chicago, Chicago, United States.

Cinkate Pharmaceutical Corp, ZhangJiang District, Shanghai, China.

出版信息

Elife. 2023 Oct 25;12:e85862. doi: 10.7554/eLife.85862.

Abstract

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, ()-19-[(1'-benzoyloxy-1'-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.

摘要

胰腺癌是全球第七大癌症相关死亡原因,尽管在疾病管理方面取得了进展,但 5 年生存率仅为 12%。雷公藤红素对包括胰腺癌在内的多种癌症具有强大的抗肿瘤活性,但其溶解度差和毒性限制了其转化为临床应用。我们合成了一种雷公藤红素的新型前药()-19-[(1′-苯甲酰氧基-1′-苯基)-亚甲基]-雷公藤红素(CK21),并将其制成乳剂,用于在大鼠和小鼠体内进行体外和体内试验,以及使用人胰腺癌细胞系和患者来源的胰腺肿瘤类器官。对 CK21 体外处理的肿瘤类器官进行了时间过程转录组谱分析,以确定其作用机制,以及体内 CK21 给药后单一时间点的转录组谱分析。静脉内给予乳化 CK21 可稳定释放雷公藤红素,并在体外对人胰腺癌细胞系和患者来源的胰腺肿瘤类器官具有强大的抗增殖作用,而体内毒性最小。体外用 CK21 处理的肿瘤类器官的时间过程转录组谱分析显示,在 3 小时时有 <10 个差异表达基因(DEG),在 12 小时时有~8000 个 DEG。观察到总体 RNA 转录抑制,Ingenuity 通路分析和功能细胞测定共同证实了 NF-κB 通路的抑制、氧化磷酸化和线粒体功能障碍的增加,最终导致活性氧(ROS)的产生增加、B 细胞淋巴瘤蛋白 2(BCL2)表达减少以及线粒体介导的肿瘤细胞凋亡。因此,CK21 是一种新型的雷公藤红素前药,通过抑制 NF-κB 通路对人胰腺肿瘤发挥强大的抗增殖作用,最终导致线粒体介导的肿瘤细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f190/10861173/5fcf37f81f54/elife-85862-fig1.jpg

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