Xu Qiong, Zhang Heng, Qin Haoren, Wang Huaqing, Wang Hui
Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin 300350, China.
School of Medicine, Nankai University, Tianjin 300350, China.
Antioxidants (Basel). 2024 Mar 14;13(3):347. doi: 10.3390/antiox13030347.
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.
去甲斑蝥素（NCTD）是斑蝥素的衍生物，可诱导活性氧（ROS）生成，被广泛用于治疗结直肠癌（CRC）。在本研究中，我们阐明了去甲斑蝥素增强CRC放疗敏感性的作用及作用机制。我们用NCTD（10或50 μmol/L）、电离辐射（IR，6 Gy）以及二者联合处理CRC细胞系LoVo和DLD-1，发现NCTD显著抑制CRC细胞增殖并增强其放疗敏感性。NCTD通过降低线粒体膜电位、增加线粒体膜通透性以及促进细胞色素C从线粒体释放到细胞质中来诱导ROS生成。IR与NCTD联合诱导ROS产生，激活线粒体分裂蛋白DRP1，导致线粒体分裂增加以及CRC放疗敏感性增强。NCTD还通过将细胞周期阻滞在G2/M期并降低p-CHK2、细胞周期蛋白B1和p-CDC2表达来降低CRC细胞对放疗的抗性。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CRC的潜在治疗用途提供了证据。此外，本研究阐明了NCTD是否能克服CRC辐射耐受性，并深入探讨了其潜在机制。
