The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Int J Mol Sci. 2023 Mar 4;24(5):4966. doi: 10.3390/ijms24054966.
Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.
硫氧还蛋白还原酶（TrxR）的抑制是抗肿瘤药物发现的关键策略。6-姜酚（6-S）是生姜中的主要生物活性化合物，具有很强的抗癌活性。然而，其潜在的作用机制尚未得到深入研究。在这项研究中，我们首次证明 6-S，一种新型的 TrxR 抑制剂，可促进 HeLa 细胞中氧化应激介导的细胞凋亡。生姜的另外两种成分，6-姜醇（6-G）和 6-去氢姜二酮（6-DG），与 6-S 具有相似的结构，但在低浓度下不能杀死 HeLa 细胞。6-S 特异性地通过靶向硒代半胱氨酸残基来抑制纯化的 TrxR1 活性。它还诱导细胞凋亡，对 HeLa 细胞的细胞毒性比正常细胞更强。6-S 介导的细胞凋亡的分子机制涉及 TrxR 抑制，随后活性氧（ROS）的爆发。此外，TrxR 敲低增强了 6-S 细胞的细胞毒性敏感性，突出了 6-S 靶向 TrxR 的生理意义。我们的研究结果表明，6-S 通过靶向 TrxR 揭示了 6-S 生物活性的新机制，并为其在癌症治疗中的作用提供了有意义的见解。
