title: Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization.
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.
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: KangAe
authors.initials: K
authors.lastname: Lee
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhang
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
authors.forename: Sergio
authors.initials: S
authors.lastname: Rey
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000167:Acriflavine / Q000493:pharmacokinetics / Q000494:pharmacology*; D019943:Amino Acid Substitution; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: C497396:ARNT protein, human; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000167:Acriflavine