Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways
| Autor: | Kaleem A. Mohammed, Yu-Dong Zhou, Yang Liu, Mika B. Jekabsons, Coothan K. Veena, J. Brian Morgan, Dale G. Nagle |
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| Rok vydání: | 2009 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male Vascular Endothelial Growth Factor A Umbilical Veins Cell Survival Blotting Western Cell Respiration Breast Neoplasms Enzyme-Linked Immunosorbent Assay Mitochondrion Biology Biochemistry chemistry.chemical_compound Oxygen Consumption Cell Movement Humans Protein kinase A Molecular Biology Transcription factor Cells Cultured Cell Proliferation Glucose Transporter Type 1 Wound Healing Neovascularization Pathologic Tumor hypoxia Cell growth Chemotaxis Mechanisms of Signal Transduction Prostatic Neoplasms Fabaceae Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit Alpinumisoflavone Isoflavones Small molecule Cell Hypoxia Mitochondria Cell biology Vascular endothelial growth factor A chemistry Protein Biosynthesis Endothelium Vascular |
| Zdroj: | Journal of Biological Chemistry. 284:5859-5868 |
| ISSN: | 0021-9258 |
| Popis: | Hypoxia is a common feature of solid tumors, and the extent of tumor hypoxia correlates with advanced disease stages and treatment resistance. The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective molecular target for anticancer drug discovery directed at tumor hypoxia. A natural product chemistry-based approach was employed to discover small molecule inhibitors of HIF-1. Bioassay-guided isolation of an active lipid extract of the tropical legumaceous plant Lonchocarpus glabrescens and structure elucidation afforded two new HIF-1 inhibitors: alpinumisoflavone (compound 1) and 4′-O-methylalpinumisoflavone (compound 2). In human breast tumor T47D cells, compounds 1 and 2 inhibited hypoxia-induced HIF-1 activation with IC50 values of 5 and 0.6 μm, respectively. At the concentrations that in hibited HIF-1 activation, compound 2 inhibited hypoxic induction of HIF-1 target genes (CDKN1A, GLUT-1, and VEGF), tumor angiogenesis in vitro, cell migration, and chemotaxis. Compound 2 inhibits HIF-1 activation by blocking the induction of nuclear HIF-1α protein, the oxygen-regulated subunit that controls HIF-1 activity. Mechanistic studies indicate that, unlike rotenone and other mitochondrial inhibitors, compound 2 represents the first small molecule that inhibits HIF-1 activation by simultaneously suppressing mitochondrial respiration and disrupting protein translation in vitro. This unique mechanism distinguishes compound 2 from other small molecule HIF-1 inhibitors that are simple mitochondrial inhibitors or flavanoid-based protein kinase inhibitors. |
| Databáze: | OpenAIRE |
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