BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I.
BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I.
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DOI：
10.1002/cam4.112
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发表时间：
2013-10
期刊：
影响因子：
4
通讯作者：
Ziegelbauer, Karl
中科院分区：
文献类型：
--
作者：
Ellinghaus, Peter;Heisler, Iring;Unterschemmann, Kerstin;Haerter, Michael;Beck, Hartmut;Greschat, Susanne;Ehrmann, Alexander;Summer, Holger;Flamme, Ingo;Oehme, Felix;Thierauch, Karlheinz;Michels, Martin;Hess-Stumpp, Holger;Ziegelbauer, Karl
转录因子缺氧诱导因子-1（HIF-1）的激活在肿瘤的发生、发展以及对化疗和放疗的抵抗中起着至关重要的作用。为了鉴定靶向HIF途径的化合物，在缺氧条件下使用内切酶驱动的HIF-1报告细胞系筛选小分子文库。高通量筛选鉴定出一类氨烷基取代的化合物，这些化合物在低纳摩尔浓度下抑制人肺癌细胞系中缺氧诱导的HIF-1靶基因表达。在低氧条件下，发现先导结构BAY 87-2243抑制非小细胞肺癌（NSCLC）细胞系H460中HIF-1α和HIF-2α蛋白的积累，但对低氧模拟物去铁胺或氯化钴诱导的HIF-1α蛋白水平没有影响。BAY 87-2243对缺乏Von Hippel-Lindau（VHL）活性的RCC 4细胞中的HIF靶基因表达水平没有影响，该化合物也不影响HIF脯氨酰羟化酶-2的活性。在H460异种移植模型中证实了BAY 87-2243的抗肿瘤活性、HIF-1α蛋白水平的抑制和HIF-1靶基因表达的体内降低。BAY 87-2243在标准条件下不抑制细胞增殖。然而，在葡萄糖耗尽（一种有利于线粒体ATP生成作为能量来源的条件）下，BAY 87-2243在纳摩尔范围内抑制细胞增殖。进一步的实验表明，BAY 87-2243抑制线粒体复合物I活性，但对复合物III活性没有影响。干扰线粒体功能以降低肿瘤中缺氧诱导的HIF-1活性可能是克服缺氧肿瘤的化疗和放疗抗性的一种有趣的治疗方法。
The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel–Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors.
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