Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization (Retracted Article)
Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization (Retracted Article)
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DOI：
10.1073/pnas.0909353106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Lee, KangAe;Zhang, Huafeng;Semenza, Gregg L.
HIF-1是一种异源二聚体转录因子，介导对缺氧的适应性反应，并在癌症进展中起关键作用。使用基于细胞的筛选测定，我们已经鉴定了吖啶黄素作为直接结合HIF-1 α和HIF-2 α并抑制HIF-1二聚化和转录活性的药物。用吖啶黄预处理携带前列腺癌异种移植物的小鼠可防止肿瘤生长，而治疗携带已建立肿瘤的小鼠可导致生长停滞。吖啶黄治疗抑制肿瘤内血管生成细胞因子的表达，血管生成细胞动员到外周血中，和肿瘤血管化。这些结果提供了小分子可以抑制HIF-1的二聚化并对肿瘤生长和血管形成具有有效抑制作用的原理证明。
HIF-1 is a heterodimeric transcription factor that mediates adaptive responses to hypoxia and plays critical roles in cancer progression. Using a cell-based screening assay we have identified acriflavine as a drug that binds directly to HIF-1 alpha and HIF-2 alpha and inhibits HIF-1 dimerization and transcriptional activity. Pretreatment of mice bearing prostate cancer xenografts with acriflavine prevented tumor growth and treatment of mice bearing established tumors resulted in growth arrest. Acriflavine treatment inhibited intratumoral expression of angiogenic cytokines, mobilization of angiogenic cells into peripheral blood, and tumor vascularization. These results provide proof of principle that small molecules can inhibit dimerization of HIF-1 and have potent inhibitory effects on tumor growth and vascularization.