期刊
ONCOGENE
卷 31, 期 2, 页码 213-225出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.228
关键词
Wnt/beta-catenin; iron; iron chelator; drug therapy; mouse models of cancer
资金
- Duke-NUS
- Singapore Translational Research (STaR)
- Agency for Science, Technology and Research, Singapore
- Ministry of Health, Singapore
- NIH [T32-GM007105-37]
Using a screen for Wnt/beta-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 similar to 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 beta-catenin-driven transcription. It inhibits cancer cell proliferation independently of its effect on beta-catenin signaling, as it works equally well in MMTV-PyMT tumors and diverse beta-catenin-independent cell lines. HQBA is a promising specific intracellular Fe(2+) chelator with activity against spontaneous mouse mammary cancers. Oncogene (2012) 31, 213-225; doi:10.1038/onc.2011.228; published online 13 June 2011
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