title: Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer.
abstract: Using a screen for Wnt/β-catenin inhibitors, a family of 8-hydroxyquinolone derivatives with in vivo anti-cancer properties was identified. Analysis of microarray data for the lead compound N-((8-hydroxy-7-quinolinyl) (4-methylphenyl)methyl)benzamide (HQBA) using the Connectivity Map database suggested that it is an iron chelator that mimics the hypoxic response. HQBA chelates Fe(2+) with a dissociation constant of ∼10(-19) M, with much weaker binding to Fe(3+) and other transition metals. HQBA inhibited proliferation of multiple cell lines in culture, and blocked the progression of established spontaneous cancers in two distinct genetically engineered mouse models of mammary cancer, MMTV-Wnt1 and MMTV-PyMT mice, without overt toxicity. HQBA may inhibit an iron-dependent factor that regulates cell-type-specific β-catenin-driven transcription. It inhibits cancer cell proliferation independently of its effect on β-catenin signaling, as it works equally well in MMTV-PyMT tumors and diverse β-catenin-independent cell lines. HQBA is a promising specific intracellular Fe(2+) chelator with activity against spontaneous mouse mammary cancers.
authors.affiliation: Program in Cancer and Stem Cell Biology , Duke-NUS Graduate Medical School, Singapore.
authors.forename: G S
authors.initials: GS
authors.lastname: Coombs
authors.forename: A A
authors.initials: AA
authors.lastname: Schmitt
authors.forename: C A
authors.initials: CA
authors.lastname: Canning
authors.forename: A
authors.initials: A
authors.lastname: Alok
authors.forename: I C C
authors.initials: IC
authors.lastname: Low
authors.forename: N
authors.initials: N
authors.lastname: Banerjee
authors.forename: S
authors.initials: S
authors.lastname: Kaur
authors.forename: V
authors.initials: V
authors.lastname: Utomo
authors.forename: C M
authors.initials: CM
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Pervaiz
authors.forename: E J
authors.initials: EJ
authors.lastname: Toone
authors.forename: D M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005296:Ferrous Compounds / Q000378:metabolism*; D005818:Genetic Engineering; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D051153:Wnt Proteins; D051176:beta Catenin