Norcantharidin (NCTD), a cantharidin derivative, induces ROS generation and is widely used to treat CRC. In this study, we clarified the role and mechanism of action of norcantharidin in increasing CRC sensitivity to radiotherapy. We treated the CRC cell lines LoVo and DLD-1 with NCTD (10 or 50 μmol/L), ionizing radiation (IR, 6 Gy), and a combination of the two and found that NCTD significantly inhibited the proliferation of CRC cells and enhanced their sensitivity to radiotherapy. NCTD induced ROS generation by decreasing the mitochondrial membrane potential, increasing mitochondrial membrane permeability, and promoting cytochrome C release from mitochondria into the cytoplasm. IR combined with NCTD induced ROS production, which activated the mitochondrial fission protein DRP1, leading to increased mitochondrial fission and CRC sensitivity to radiotherapy. NCTD also reduced CRC cell resistance to radiotherapy by blocking the cell cycle at the G2/M phase and decreasing p-CHK2, cyclin B1, and p-CDC2 expression. NCTD and IR also inhibited radiation resistance by causing DNA damage. Our findings provide evidence for the potential therapeutic use of NCTD and IR against CRC. Moreover, this study elucidates whether NCTD can overcome CRC radiation tolerance and provides insights into the underlying mechanisms.

中文翻译：

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去甲斑蝥素通过活性氧-DRP1介导的线粒体损伤使结直肠癌细胞对放射治疗敏感


去甲斑蝥素 (NCTD) 是一种斑蝥素衍生物，可诱导 ROS 产生，广泛用于治疗结直肠癌。在这项研究中，我们阐明了去甲斑蝥素在提高结直肠癌对放疗敏感性中的作用和作用机制。我们用 NCTD（10 或 50 μmol/L）、电离辐射（IR，6 Gy）以及两者的组合处理 CRC 细胞系 LoVo 和 DLD-1，发现 NCTD 显着抑制 CRC 细胞的增殖并增强他们对放射治疗的敏感性。 NCTD 通过降低线粒体膜电位、增加线粒体膜通透性和促进细胞色素 C 从线粒体释放到细胞质中来诱导 ROS 产生。 IR 与 NCTD 结合诱导 ROS 产生，激活线粒体裂变蛋白 DRP1，导致线粒体裂变和 CRC 对放疗的敏感性增加。 NCTD 还通过阻断 G2/M 期的细胞周期并降低 p-CHK2、细胞周期蛋白 B1 和 p-CDC2 的表达来降低 CRC 细胞对放疗的抵抗力。 NCTD 和 IR 还通过引起 DNA 损伤来抑制辐射抗性。我们的研究结果为 NCTD 和 IR 对抗 CRC 的潜在治疗用途提供了证据。此外，这项研究阐明了 NCTD 是否可以克服 CRC 辐射耐受性，并提供了对其潜在机制的见解。