Lee KangAe, Zhang Huafeng, Qian David Z, Rey Sergio, Liu Jun O, Semenza Gregg L
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-5. doi: 10.1073/pnas.0909353106. Epub 2009 Oct 1.
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-1alpha and HIF-2alpha 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.
缺氧诱导因子-1（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，并在癌症进展中发挥关键作用。通过基于细胞的筛选试验，我们已确定吖啶黄是一种直接与HIF-1α和HIF-2α结合并抑制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瘤的小鼠可防止肿瘤生长，而对已形成肿瘤的小鼠进行治疗则导致生长停滞。吖啶黄治疗可抑制肿瘤内血管生成细胞因子的表达、血管生成细胞向外周血的动员以及肿瘤血管形成。这些结果提供了小分子可抑制HIF-1二聚化并对肿瘤生长和血管形成具有强效抑制作用的原理证明。
