College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, South Korea; Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.
Institute of Natural Medicine, Hallym University, Chuncheon, 24252, South Korea.
Biomed Pharmacother. 2021 Jan;133:111082. doi: 10.1016/j.biopha.2020.111082. Epub 2020 Dec 4.
Hypoxia-inducible factor (HIF)-1 is an important regulator of the cellular response in the hypoxic tumor environment. While searching for HIF inhibitors derived from natural products that act as anticancer agents, we found that Glycyrrhiza uralensis exerts HIF-1 inhibitory activity in hypoxic cancer cells. Among the five components of G. uralensis, licochalcone A was found to potently suppress hypoxia-induced HIF-1α accumulation and expression of HIF-1α target genes, including GLUT1 and PDK1 in HCT116 cells. Licochalcone A also enhances intracellular oxygen content by directly inhibiting mitochondrial respiration, resulting in oxygen-dependent HIF-1α degradation. Hence, licochalcone A may effectively inhibit ATP production, primarily by reducing the mitochondrial respiration-mediated ATP production rate rather than the glycolysis-mediated ATP production rate. This effect subsequently suppresses cancer cell viability, including that of HCT116, H1299, and H322 cells. Consequently, these results suggest that licochalcone A has therapeutic potential in hypoxic cancer cells.
缺氧诱导因子 (HIF)-1 是缺氧肿瘤微环境中细胞反应的重要调节剂。在寻找源自天然产物的 HIF 抑制剂作为抗癌剂时，我们发现甘草对缺氧癌细胞具有 HIF-1 抑制活性。在甘草的五种成分中，甘草查尔酮 A 被发现能够强烈抑制缺氧诱导的 HIF-1α 积累和 HIF-1α 靶基因的表达，包括 HCT116 细胞中的 GLUT1 和 PDK1。甘草查尔酮 A 还通过直接抑制线粒体呼吸来增加细胞内氧含量，导致氧依赖性 HIF-1α 降解。因此，甘草查尔酮 A 可能通过降低线粒体呼吸介导的 ATP 产生速率而不是糖酵解介导的 ATP 产生速率来有效抑制 ATP 产生。这种作用随后抑制了包括 HCT116、H1299 和 H322 细胞在内的癌细胞活力。因此，这些结果表明甘草查尔酮 A 对缺氧癌细胞具有治疗潜力。
