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首页> 外文期刊>Journal of experimental & clinical cancer research : >Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development.
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Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development.

机译：细胞氧化还原状态调节缺氧诱导因子-1活性。在肿瘤发展中的作用。

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The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 100 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodelling, inflammation, and hypoxia/ischemia-related tissue damage. Experimental data support the concept that modulation of Reactive Oxygen Species (ROS) levels have an important impact on the hypoxic response mediated by HIF-1 alpha. However, ROS generation, the exact kinetics and conditions of ROS production and their specific relevance to HIF-l alpha activation are issue still to be clarified. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for anti-tumour drug discovery. Considerable effort is underway to identify therapeutically useful molecule HIF-1 inhibitors. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Many of the substances found to inhibit HIF-I are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.
机译：转录因子低氧诱导因子-1（HIF-1）调节了100多个参与低氧胁迫下细胞适应和存活的基因的表达。 HIF-1的激活与许多生理和病理过程相关，包括肿瘤发生，血管重塑，炎症和缺氧/缺血相关的组织损伤。实验数据支持以下概念：活性氧（ROS）水平的调节对HIF-1 alpha介导的低氧反应具有重要影响。然而，尚需阐明ROS的产生，ROS产生的确切动力学和条件以及它们与HIF-1α活化的特定相关性。临床研究表明，HIF-1激活与癌症患者的晚期疾病阶段和治疗耐药性直接相关。临床前研究支持抑制HIF-1作为抗肿瘤药物发现的主要分子靶标。正在进行大量努力以鉴定治疗上有用的分子HIF-1抑制剂。被发现抑制HIF-1的大多数化合物是天然产物或具有基于天然产物前导结构的合成化合物。天然产物还作为分子探针阐明调节HIF-1活性的途径发挥了至关重要的作用。被发现抑制HIF-1的许多物质都是不可药物性的化合物，其细胞毒性太大，无法用作药物前导。高通量筛选方法，互补分子靶向测定法和结构多样的化学文库的应用为发现治疗上有用的HIF-1抑制剂提供了希望。

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