Ma Ji, Zheng Liyun, Fang Shiji, Yang Wenjing, Ding Yiming, Wang Mengyuan, Chen Jiale, Weng Qiaoyou, Yao Zouying, Jiang Chuan, Chen Minjiang, Xu Hongtao, Ji Jiansong
Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Department of radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China; Department of Gastrointestinal surgery, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Department of radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
Transl Oncol. 2025 Oct;60:102491. doi: 10.1016/j.tranon.2025.102491. Epub 2025 Aug 6.
Oxaliplatin (OXA) is a common chemotherapeutic agent for advanced colorectal cancer. However, its effectiveness is limited by drug resistance, highlighting the need for combination therapies. In this study, Triptonide (TN), a diterpenoid compound is used to enhance the sensitivity of OXA, and the underlying mechanisms are investigated. Our findings indicated the combination of TN and OXA demonstrated strong synergistic anti-tumor effects across a broad concentration range in both HCT116 and LoVo cell lines, particularly at ratios ranging from 1:312 to 1:156. The combination of TN and OXA at low doses effectively inhibits growth and induces cell death in HCT116 and LoVo cells. TN and OXA cotreatment causes severe mitochondrial damage in colorectal cancer cells, leading to intracellular reactive oxygen species (ROS) accumulation, which subsequently triggers apoptosis and ferroptosis. Mechanistically, TN directly binds to BIM, a pro-apoptotic and ferroptotic protein, and stabilizes it. TN treatment led to increased expression of BIM and knockdown of BIM alleviated the growth inhibition of OXA in colorectal cancer cells. Finally, TN and OXA cotreatment significantly reduced the tumor weight and volume of LoVo-bearing nude mice in vivo. Taken together, our findings indicate that TN may serve as a novel therapeutic agent to enhance the efficacy OXA in the treatment of colorectal cancer.
奥沙利铂（OXA）是一种用于晚期结直肠癌的常用化疗药物。然而，其疗效受到耐药性的限制，这凸显了联合治疗的必要性。在本研究中，使用二萜类化合物雷公藤内酯醇（TN）来增强奥沙利铂的敏感性，并研究其潜在机制。我们的研究结果表明，在HCT116和LoVo细胞系中，TN与奥沙利铂的联合在广泛的浓度范围内均表现出强大的协同抗肿瘤作用，特别是在1:312至1:156的比例范围内。低剂量的TN与奥沙利铂联合可有效抑制HCT116和LoVo细胞的生长并诱导细胞死亡。TN与奥沙利铂联合处理会导致结肠癌细胞发生严重的线粒体损伤，导致细胞内活性氧（ROS）积累，进而引发细胞凋亡和铁死亡。机制上，TN直接与促凋亡和铁死亡蛋白BIM结合并使其稳定。TN处理导致BIM表达增加，而敲低BIM可减轻奥沙利铂对结肠癌细胞生长的抑制作用。最后，TN与奥沙利铂联合处理在体内显著降低了荷LoVo裸鼠的肿瘤重量和体积。综上所述，我们的研究结果表明，TN可能作为一种新型治疗药物来增强奥沙利铂在结直肠癌治疗中的疗效。
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