Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Acriflavine / pharmacokinetics
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Acriflavine / pharmacology*
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Amino Acid Substitution
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Angiogenesis Inhibitors / pharmacokinetics
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Angiogenesis Inhibitors / pharmacology
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Animals
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Aryl Hydrocarbon Receptor Nuclear Translocator / chemistry*
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism*
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Base Sequence
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Binding Sites
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Cell Line
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism
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Dimerization
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / chemistry*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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In Vitro Techniques
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Male
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Mice
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Mice, SCID
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Neovascularization, Pathologic / prevention & control
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Prostatic Neoplasms / blood supply
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology
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Protein Structure, Quaternary / drug effects
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Transcription, Genetic / drug effects
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Transplantation, Heterologous
Substances
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ARNT protein, human
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Angiogenesis Inhibitors
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Antineoplastic Agents
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DNA, Neoplasm
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Neoplasm Proteins
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Recombinant Proteins
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Aryl Hydrocarbon Receptor Nuclear Translocator
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Acriflavine