Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Division of Cancer Genome Research, German Cancer Research Center (DKFZ) Heidelberg, National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership between DKFZ and University Hospital, 69120 Heidelberg, Germany.
Int J Mol Sci. 2024 Mar 7;25(6):3087. doi: 10.3390/ijms25063087.
Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.
萘基异喹啉（NIQ）生物碱是一类具有药物潜力的新兴次生代谢产物，越来越受到关注。NF-κB 已被认为是癌症增殖和耐药性的重要调节剂。我们之前报道了单体 Dioncophylline A 对白血病细胞细胞毒性作用的机制，Dioncophylline A 是一种 NIQ 单体。在本研究中，我们研究了 NIQ 二聚体 Joziimine A 对白血病细胞的细胞毒性作用，并将其与第二种结构不对称的二聚体 Michellamine B 进行了比较。为此，应用分子对接预测二聚体与 NF-κB 的结合亲和力，然后通过微尺度热泳法进行验证。接下来，在 CCRF-CEM 细胞和多药耐药 CEM/ADR5000 细胞中进行了细胞毒性测定。转录组分析揭示了 Joziimine A 影响的分子网络，并确定细胞周期是受主要影响的过程之一。通过流式细胞术评估细胞死亡模式，用人脐静脉内皮细胞（HUVEC）的内皮细胞管形成测定法测量血管生成。结果表明，Jozimine A 与 NF-κB 结合，抑制其活性并阻止其向核内易位。此外，Jozimine A 通过细胞凋亡诱导细胞死亡并阻止血管生成。本研究描述了 Joziimine A 对白血病细胞的细胞毒性作用，并解释了与 NF-κB 信号通路和抗癌活性的相互作用。
Zotero 插件
