通过 DNA 双链断裂的表型筛选发现新型 DNA 损伤剂,Cancer Science

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通过 DNA 双链断裂的表型筛选发现新型 DNA 损伤剂
Cancer Science ( IF 4.5 ) Pub Date : 2022-11-16 , DOI: 10.1111/cas.15659
Doudou Zhang ₁ , Takashi Shimokawa ₂ , Qianqian Guo _{1,

3} , Shingo Dan ₄ , Yoshio Miki ₁ , Shigeaki Sunada _{1,

3,

5}

Affiliation

DNA 双链断裂 (DSB) 会严重损害 DNA 并促进基因组不稳定，从而导致细胞死亡。它们是致癌和衰老等疾病的根源，但在癌症治疗中也有重要应用。因此，细胞中 DSB 的快速检测和定量对于鉴定致癌和抗癌因子是必要的。在这项研究中，我们使用基于流式细胞术的高通量方法检测 DSB，以分析 γH2AX 强度。我们筛选了一个包含 9600 种化合物的化学库，并检测到多种 DNA 损伤化合物，尽管我们无法通过该程序确定作用机制。因此，我们还使用我们称为“分子分析”的基于生物信息学的方法分析了具有最高 DSB 潜力的代表性化合物 DNA 损伤剂 1 (DDA-1)。预测和验证分析表明 DDA-1 是一种潜在的拓扑异构酶 IIα 抑制剂，不同于依托泊苷和多柔比星等已知抑制剂。对 DDA-1 类似物和异种移植模型的进一步研究表明，DDA-1 是一种潜在的抗癌药物。总之，我们的研究结果表明，结合高通量 DSB 检测和分子谱分析进行表型分析是一种有效鉴定用于临床应用的新型 DNA 损伤化合物的可行方法。

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Discovery of novel DNA-damaging agents through phenotypic screening for DNA double-strand break

DNA double-strand breaks (DSBs) seriously damage DNA and promote genomic instability that can lead to cell death. They are the source of conditions such as carcinogenesis and aging, but also have important applications in cancer therapy. Therefore, rapid detection and quantification of DSBs in cells are necessary for identifying carcinogenic and anticancer factors. In this study, we detected DSBs using a flow cytometry-based high-throughput method to analyze γH2AX intensity. We screened a chemical library containing 9600 compounds and detected multiple DNA-damaging compounds, although we could not identify mechanisms of action through this procedure. Thus, we also profiled a representative compound with the highest DSB potential, DNA-damaging agent-1 (DDA-1), using a bioinformatics-based method we termed “molecular profiling.” Prediction and verification analysis revealed DDA-1 as a potential inhibitor of topoisomerase IIα, different from known inhibitors such as etoposide and doxorubicin. Additional investigation of DDA-1 analogs and xenograft models suggested that DDA-1 is a potential anticancer drug. In conclusion, our findings established that combining high-throughput DSB detection and molecular profiling to undertake phenotypic analysis is a viable method for efficient identification of novel DNA-damaging compounds for clinical applications.

更新日期：2022-11-16

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