Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.

TitleInhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.
Publication TypeJournal Article
Year of Publication2013
AuthorsWelsh SJ, Dale AG, Lombardo CM, Valentine H, de la Fuente M, Schätzlein A, Neidle S
JournalSci Rep
Date Published2013
KeywordsAnimals, Blotting, Western, Carcinogens, Carcinoma, Renal Cell, Cell Hypoxia, Female, G-Quadruplexes, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoenzyme Techniques, Kidney Neoplasms, Mice, Mice, Nude, Promoter Regions, Genetic, Real-Time Polymerase Chain Reaction, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Small Molecule Libraries, Transcriptional Activation, Tumor Cells, Cultured, Xenograft Model Antitumor Assays

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.

Alternate JournalSci Rep
PubMed ID24165797
PubMed Central IDPMC3810677