Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development.
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.
Martínez-Sánchez
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Centre for Research and Biological Evaluations, Institute of Pharmacy and Food Science, University of Havana, Havana, Cuba. gregorioms@informed.sld.cu
Giuliani
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D010100:Oxygen