Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways
Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways
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DOI：
10.1074/jbc.m806744200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Zhou, Yu-Dong
中科院分区：
文献类型：
--
作者：
Liu, Yang;Veena, Coothan K.;Zhou, Yu-Dong
缺氧是实体瘤的共同特征，并且肿瘤缺氧的程度与晚期疾病阶段和治疗抵抗相关。缺氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）是一种重要的肿瘤选择性分子靶点，可用于肿瘤缺氧靶点的抗肿瘤药物开发。采用基于天然产物化学的方法来发现HIF-1的小分子抑制剂。从热带豆科植物光叶龙柏（Lonchocarpus glabrescens）中提取活性脂质，经生物活性测定和结构鉴定，得到两种新的HIF-1抑制剂：alpinumalate（化合物1）和4 '-O-methylalpinumalate（化合物2）。在人乳腺肿瘤T47 D细胞中，化合物1和2抑制缺氧诱导的HIF-1活化，IC 50值分别为5和0.6 μ M。在抑制HIF-1活化的浓度下，化合物2抑制HIF-1靶基因（CDKN 1A、GLUT-1和VEGF）的缺氧诱导、体外肿瘤血管生成、细胞迁移和趋化性。化合物2通过阻断核HIF-1 α蛋白的诱导来抑制HIF-1活化，所述核HIF-1 α蛋白是控制HIF-1活性的氧调节亚基。机制研究表明，与鱼藤酮和其他线粒体抑制剂不同，化合物2代表了第一个通过同时抑制线粒体呼吸和破坏体外蛋白质翻译来抑制HIF-1活化的小分子。这种独特的机制将化合物2与其他小分子HIF-1抑制剂区分开来，所述其他小分子HIF-1抑制剂是简单的线粒体抑制剂或基于类黄酮的蛋白激酶抑制剂。
Hypoxia is a common feature of solid tumors, and the extent of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective molecular target for anticancer drug discovery directed at tumor hypoxia. A natural product chemistry-based approach was employed to discover small molecule inhibitors of HIF-1. Bioassay-guided isolation of an active lipid extract of the tropical legumaceous plant Lonchocarpus glabrescens and structure elucidation afforded two new HIF-1 inhibitors: alpinumisoflavone (compound 1) and 4'-O-methylalpinumisoflavone (compound 2). In human breast tumor T47D cells, compounds 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC50 values of 5 and 0.6 mu M, respectively. At the concentrations that inhibited HIF-1 activation, compound 2 inhibited hypoxic induction of HIF-1 target genes (CDKN1A, GLUT-1, and VEGF), tumor angiogenesis in vitro, cell migration, and chemotaxis. Compound 2 inhibits HIF-1 activation by blocking the induction of nuclear HIF-1 alpha protein, the oxygen-regulated subunit that controls HIF-1 activity. Mechanistic studies indicate that, unlike rotenone and other mitochondrial inhibitors, compound 2 represents the first small molecule that inhibits HIF-1 activation by simultaneously suppressing mitochondrial respiration and disrupting protein translation in vitro. This unique mechanism distinguishes compound 2 from other small molecule HIF-1 inhibitors that are simple mitochondrial inhibitors or flavanoid-based protein kinase inhibitors.