State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Redox Biol. 2023 Aug;64:102785. doi: 10.1016/j.redox.2023.102785. Epub 2023 Jun 14.
There are no effective therapeutic targets or strategies that simultaneously inhibit tumour growth and promote cardiac function recovery. Here, we analyzed targets for cancer treatments and cardiac repair, with demethylation emerging as a common factor in these candidate lists. As DNA methyltransferase 1 (DNMT1) majorly responds to methylation, a natural compound library is screened, identifying dioscin as a novel agent targeted at DNMT1, widely used for heart diseases. Dioscin was found to reduce DNMT activities and inhibits growth in breast cancer cells. Combined with analyses of RNA-seq and MeDIP-seq, the promoters of antioxidant genes were demethylated after dioscin, recruiting NRF2 and elevating their expression. In Nrf2 knockout mice, the cardiac protection role of dioscin was blocked by Nrf2-loss. Furthermore, in tumour-bearing mice with hypertrophy, dioscin was observed to inhibit tumour growth and alleviate cardiac injury simultaneously. This study is the first to identify dioscin as a novel demethylation agent with dual functions of anti-cancer and cardio-protection.
目前尚无同时抑制肿瘤生长和促进心脏功能恢复的有效治疗靶点或策略。在这里，我们分析了癌症治疗和心脏修复的靶点，去甲基化是这些候选靶点中的一个共同因素。由于 DNA 甲基转移酶 1（DNMT1）主要响应于甲基化，我们筛选了天然化合物库，发现薯蓣皂苷元是一种针对 DNMT1 的新型药物，广泛用于心脏病。薯蓣皂苷元被发现可降低 DNMT 活性并抑制乳腺癌细胞生长。结合 RNA-seq 和 MeDIP-seq 分析，薯蓣皂苷元处理后抗氧化基因的启动子被去甲基化，募集 NRF2 并提高其表达。在 Nrf2 敲除小鼠中，Nrf2 缺失阻断了薯蓣皂苷元的心脏保护作用。此外，在荷瘤肥大小鼠中，薯蓣皂苷元被观察到可同时抑制肿瘤生长和减轻心脏损伤。本研究首次鉴定出薯蓣皂苷元是一种具有抗癌和心脏保护双重功能的新型去甲基化剂。
