Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China.
State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming 650500, China.
Int J Mol Sci. 2024 Sep 8;25(17):9717. doi: 10.3390/ijms25179717.
Due to limited drug efficacy and drug resistance, it is urgent to explore effective anti-liver cancer drugs. Repurposing drugs is an efficient strategy, with advantages including reduced costs, shortened development cycles, and assured safety. In this study, we adopted a synergistic approach combining computational and experimental methods and identified the antibacterial drug thiostrepton (TST) as a candidate for an anti-liver cancer drug. Although the anti-tumor capabilities of TST have been reported, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unclear. TST was found here to inhibit the proliferation of HCC cells effectively, arresting the cell cycle and inducing cell apoptosis, as well as suppressing the cell migration. Further, our findings revealed that TST induced mitochondrial impairment, which was demonstrated by destroyed mitochondrial structures, reduced mitochondria, and decreased mitochondrial membrane potential (MMP). TST caused the production of reactive oxygen species (ROS), and the mitochondrial impairment and proliferation inhibition of HCC cells were completely restored by the ROS scavenger N-acetyl-L-cysteine (NAC). Moreover, we discovered that TST induced mitophagy, and autophagy inhibition effectively promoted the anti-cancer effects of TST on HCC cells. In conclusion, our study suggests TST as a promising candidate for the treatment of liver cancers, and these findings provide theoretical support for the further development and potential application of TST in clinical liver cancer therapy.
由于药物疗效有限和耐药性问题，迫切需要探索有效的肝癌治疗药物。药物再利用是一种有效的策略，具有降低成本、缩短开发周期和确保安全性的优势。在本研究中，我们采用了一种计算和实验相结合的协同方法，确定了抗菌药物硫链丝菌素（TST）是一种有希望的肝癌治疗药物候选物。尽管 TST 的抗肿瘤能力已被报道，但它在肝细胞癌（HCC）中的作用和潜在机制尚不清楚。我们发现 TST 能有效抑制 HCC 细胞的增殖，使细胞周期停滞并诱导细胞凋亡，同时抑制细胞迁移。进一步的研究结果表明，TST 诱导了线粒体损伤，这表现为线粒体结构破坏、线粒体减少和线粒体膜电位（MMP）降低。TST 引起了活性氧（ROS）的产生，ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）完全恢复了 HCC 细胞的线粒体损伤和增殖抑制。此外，我们发现 TST 诱导了线粒体自噬，而自噬抑制有效地促进了 TST 对 HCC 细胞的抗癌作用。总之，我们的研究表明 TST 是治疗肝癌的一种有前途的候选药物，这些发现为 TST 在临床肝癌治疗中的进一步开发和潜在应用提供了理论支持。
