Modulation of Wnt/β-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer
MetadataShow full item record
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 Fe2+ with a dissociation constant of ~10-19 M, with much weaker binding to Fe3+ 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 Fe2+ chelator with activity against spontaneous mouse mammary cancers.
Showing items related by title, author, creator and subject.
Vincan, Elizabeth; Flanagan, D.; Pouliot, N.; Brabletz, T.; Spaderna, S. (2010)Recent evidence shows that a sub-population of Wnt/ß-catenin target genes is specifically induced in different tissue contexts. FZD7 is a putative Wnt/ß-catenin target gene and although it is highly expressed in ...
Yu, W.; Yu, Yu; Richardson, D. (2011)Previous studies demonstrated that thiosemicarbazone iron chelator possessed potent and selective anti-cancer activity. In this study, the in vitro and in vivo anti-tumor efficacy and tolerability of 2-benzoylpyridine ...
Yu, Yu; Gutierrez, E.; Kovacevic, Z.; Saletta, F.; Obeidy, P.; Rahmanto, Y.; Richardson, D. (2012)The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also ...