Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells
Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells
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Adenanthin 靶向过氧化还原蛋白 I 和 II 诱导白血病细胞分化
DOI：
10.1038/nchembio.935
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发表时间：
2012-05-01
影响因子：
14.8
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
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作者：
Liu, Chuan-Xu;Yin, Qian-Qian;Chen, Guo-Qiang
过氧化物酶（Peroxiredoxins，Prxs）是治疗癌症等重大疾病的潜在靶点。然而，同种型特异性抑制剂仍有待开发。我们报道了一种从腺花香茶菜叶中分离的二萜类化合物，腺黄素诱导急性早幼粒细胞白血病（APL）细胞分化。我们表明，腺嘌呤直接针对保守的解决半胱氨酸的Prx I和Prx II，并抑制其过氧化物酶活性。因此，细胞H2 O2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。腺嘌呤核苷诱导APL样细胞分化，抑制体内肿瘤生长，并延长对维甲酸敏感和耐药的小鼠APL模型的存活。因此，腺嘌呤可以作为什么是我们所知的第一个铅天然化合物的Prx I和Prx II靶向治疗药物的发展，这可能是一个有前途的方法来诱导APL细胞分化。
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 H2O2 is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein beta, 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.