title: Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.
abstract: The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression.
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Welsh
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Dale
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Lombardo
authors.forename: Helen
authors.initials: H
authors.lastname: Valentine
authors.forename: Maria
authors.initials: M
authors.lastname: de la Fuente
authors.forename: Andreas
authors.initials: A
authors.lastname: Schatzlein
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects*; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002273:Carcinogens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D054852:Small Molecule Libraries