Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Chem Biol. 2012 Apr 8;8(5):486-93. doi: 10.1038/nchembio.935.
Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein β, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.
过氧化物酶（Prxs）是癌症等重大疾病的潜在治疗靶点。然而，同型特异性抑制剂仍有待开发。我们报告称，从 Rabdosia adenantha 叶中分离得到的二萜类化合物腺嘌呤能诱导急性早幼粒细胞白血病（APL）细胞分化。我们表明，腺嘌呤能直接靶向 Prx I 和 Prx II 的保守解旋半胱氨酸并抑制其过氧化物酶活性。因此，细胞内 H₂O₂升高，导致细胞外信号调节激酶的激活和 CCAAT/增强子结合蛋白 β 的转录增加，这有助于腺嘌呤诱导的分化。腺嘌呤诱导 APL 样细胞分化，体内抑制肿瘤生长，并延长对维甲酸敏感和耐药的小鼠 APL 模型的存活时间。因此，腺嘌呤可以作为我们所知的第一个针对 Prx I 和 Prx II 靶向治疗剂的先导天然化合物，这可能代表了诱导 APL 细胞分化的一种很有前途的方法。
